Induction of drug-metabolizing enzymes by insecticides and other xenobiotics

Pharmac.Ther.Vol. 11, pp. 43 107

0163 7258/80/0801 0043505.00/0

© PergamonPressLtd. Printed in Great Britain

Specialist Subject Editor: FUMIO MATSUMURA

INDUCTION OF DRUG-METABOLIZING ENZYMES BY INSECTICIDES AND OTHER XENOBIOTICS*

M. A. Q. KHAN Department of Biological Sciences, University of Illinois at Chicago Circle, Box 4348, Chicago, Illinois 60680

1. INTRODUCTION The intensity of the toxic manifestation of an insecticidal chemical depends on the dosage of the toxic principle that eventually reaches the site of toxic action. This depends on the metabolic alteration of the parent chemical as well as on the transport of the toxicophore to the target site. Unless the site of action of the insecticidal chemical is at the site of entry and/or the insecticide is refractive to biotransformation, its effect in the animal depends on its alteration which takes place mainly in the liver. The levels of activity of the hepatic detoxication enzymes called Drug-Metabolizing Enzymes (DME) or Mixed-Function Oxygenases (MFO) determine the nature and extent of metabolism and thus action and fate of the insecticide in the animal. The hepatic DME can be controlled genetically and probably by non-nuclear factors. Their synthesis occurs throughout the life of the organism because of their limited life (7 to 100 hrs) (Maines, 1977; Arias et al., 1969b). Their levels and activity in the same species can sometimes be altered by internal factors such as age, sex, diet, hormonal changes (Kato and Gillette, 1965; Colas et al., 1969; Lang and Hanninen, 1977; Kahl et al., 1977; Down and Chasseaud, 1978; Gram et al., 1977; Noordhoek et al., 1977) or by external factors, such as light, temperature, oxygen concentration, foreign chemicals, etc. (Rosenthal et al., 1977; Kahl et al., 1977; Conney and Burns, 1972; Kappas et al., 1977; Merritt and Medina, 1968; Conney, 1967; Gillette, 1963; Fours, 1963). This review will address itself to the effects of insecticides and other foreign chemicals on detoxication enzymes especially those involved in the insecticide toxicity and metabolism, i.e. Drug Metabolizing Enzymes (DME) or Mixed-Function Oxygenases (MFO). These enzymes can metabolize more than three hundred chemicals including pesticides, carcinogens, drugs, steroids, environmental pollutants (Mannering, 1972). The amount of an enzyme (protein) may be controlled by factors affecting the rate of enzyme synthesis and/or the rate of enzyme breakdown. The term enzyme induction will be used specifically to describe 'the process which increases the rate of synthesis of an enzyme relative to its normal rate of synthesis in individuals not pre-treated with any foreign chemical that can induce the enzyme synthesis (Gelboin, 1972).' Exposure of mammals to foreign chemicals such as insecticides, polycyclic aryl hydrocarbons, barbiturates (Table 1) can result in an increase in the size of the liver. This increase in the size of hepatocytes is accompanied by an increase in the synthesis of proteins which, in the case of phenobarbital and related compounds (phenylbutazone, chloryclazine, ophenadrin), occurs mostly in the smooth endoplasmic reticulum (SER) leading to 22-39 per cent higher amount of protein per gm wet wt. of liver (Fouts and Rogers, 1965; Returner and Merker, 1963; Arcos et al., 1961; Conney and Gilman, 1963; Conaway et al., 1977; Schulte-Hermann, 1974, 1977a; Park, 1979). These alterations in hepatic ultrastructure and biochemistry increase the concentration of the DMEs in *Supported by a USPHS grant ES-01479 from National Institute of Environmental Health Sciences. Excellent help in typing by Pat Kelly and Karen Hohne is gratefully acknowledged. 43

44

M . A . Q . KHAN

microsomes which occur on the SER. This eventually results in an increased rate of bioalteration of foreign chemical(s) by the organism thereby altering its response to the particular chemical(s). Although a large number of compounds of different molecular types may increase the same enzyme system, there are a number of enzymes which are increased by one class of compounds and not by another (Table 2). The threshold dosage for induction of D M E depends on the chemical nature and stability of the inducer whether administered orally or intraperitoneally. In rats such a threshold dose in case of intraperitoneal injection, lies between 14-20 mg per kg body wt. in the case of most effective inducers (phenobarbital--1 mg daily for 4 days, 3-methylcholanthrene 20rag for 1 day, D D T - - 1 mg for 2 days) (see: Conney and Burns, 1972; Hayes, 1975), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is one of the most effective inducers, a single 10/~g/kg dose can cause significant increase for as long as 35 days (Poland and Glover, 1974: Neal et al., 1970, 1979: Poland et al.. 1979). The inductive effect can be intensified by increasing the dosage. Inducers are generally classified in two broad classes: (a) barbiturates and related compounds, drugs and insecticides that induce a host of D M E cause intense ultrastructural changes, increase the weight of hepatocytes (cause increase synthesis of proteins, P-450, and other microsomal components) and, (b) carcinogenic polycyclic aryl hydrocarbons (BP, 3-MC) that induce specific and narrower range of enzymes which are also inducible by barbiturates, have less intense effects on the hepatic ultrastructure, cause an overall increase in the weight of hepatocytes, and cause synthesis of a new cytochrome (or P-450a) without inducing NADPH-cytochrome-c-reductase (Table 2).* A third class of chemicals includes steroids which increase the activities of reductases but not the cytochrome P-450 (Parke, 1977). The studies of induction can include: (1) Effects of inducers on pharmacologic and toxicologic action of drugs, pesticides, steroids, etc. (2) the process of induction: ultrastrtlctural effects, biochemical effects (on the in vivo and in v i t r o metabolism of drugs, pesticides, steroids, etc.), induction of specific D M E in vitro, and genetic regulation of the mechanisms(s) of induction.

1.1. EFFECTS OF INDUCERS ON DRUG TOLERANCE/ACTION Since drugs, pesticides, steroids, environmental contaminants, etc., induce hepatic D M E resulting in the increased rate of metabolism and excretion of a test drug, hormone or steroid, the duration of action of the drug or toxicant is lowered (Tables 2 and 3). Most commonly used method is to observe the effect of pretreatment on the duration of barbiturate sleeping time. If the chemical at the test dosage is inducing the hepatic D M E (which also metabolize barbiturates) the sleeping time will be shortened. Barbiturates are strong inducers of DMEs and in such a case the inductive effect on the action of the test chemical will depend on whether the product(s) formed by D M E become more active or less active. For example, induction of D M E will increase the toxicity of insecticides such as thio- and thionophosphate insecticides which are converted to more toxic analogues and lower the toxicity of carbaryl, photoisodrin, etc., which are detoxified by the D M E (O'Brien, 1967; Khan et al., 1970). A reverse effect will be seen following pretreatment with chemicals such as SKF-525A, sesamex, piperonyl butoxide, which inhibit the activity of D M E (Murphy and DuBois, 1958). The race for the production and usage of synthetic chemicals that started during World War 2 will keep gaining momentum. Not to mention the ecosystems and human health 10 years from now, the usage of certain chemicals during the last 34 years has already started showing deteriorating effects on living systems. These synthetic chemicals *There are chemicals such as isosaffoleand pregnenolone-16-a-carbonitrilewhich can induce hemoprotcin(s) P-450 posessing properties in common with the two general classes of inducers (Haugen et al., 1976; Elcombeet al., 1977; Dickins et al., 19781.

Induction of drug-metabolizing enzymes

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(present in air, water, soil, food) have become a way of life in our society which is now so dependent on these chemicals. Some of these chemicals become chronic inducers either due to constant exposure or because of their persistence in living organisms. Changes in the hepatic endoplasmic reticulum by barbiturates and chlorinated hydrocarbons have been well documented. Fouts and co-workers (Hart and Fouts, 1963; Fouts and Rogers, 1965; Fouts and Gram, 1969) have elucidated this so clearly in mammalian species, that this has become textbook information. Repeated dosages of broad-spectrum inducers (PB, OCs, tolbutamide, nikethamide, phenylbutazone, chlorcyclazine, orphenadrin) increase liver size (weight) by 20-50 per cent leading to parenchymal hypertrophy in severe cases (Fouts and Rogers, 1965; Remmer and Merker, 1963). There is an augmentation of smooth membranes without any change in the appearance of other cell structures. SER contents in induced hepatocytes are increased by 2-fold (Remmer and Merker, 1963; Fouts and Rogers, 1965). This effect is less evident in the case of animals induced with specific inducers, polycyclic aryl hydrocarbons (3MC, BP, napthacene, anthracene) (Conney, 1972; Gelboin, 1972). Chlorinated hydrocarbons such as DDT and its metabolites, cyclodienes, polychlorinated biphenyls, and TCDD, because of their persistence in the animal body, show their chronic effects on hepatic ultrastructure of mammals (Rogers and Fours, 1965; Street, 1969a; Poland and Glover, 1974; Poland et al., 1979; Neal et al., 1979), birds (Pan et al., 1975; Khan et al., 1977; Kedo et al., 1977), and fish (James et al., 1977; Bend et al., 1979). The increase in smooth endoplasmic membranes is reflected in an increase in number and size of microsomal components such as proteins (Ragnotti and Aletti, 1978), phospholipids, steroids, DME enzymes, etc. There is about a 2-fold increase in protein and lipid content in SER due to phenobarbital treatment (Arcos et al., 1961). Moderate enlargement of the liver of the individual hepatocytes is adaptive and beneficial if it is the result of an increase of SER and DMEs (Schulte-Hermann, 1974). In the case of DDT (Hoffman et al., 1970) and butylated hydroxytoluene (Gilbert and Goldberg, 1967) the adaptive response occurs over a wide range and at sufficiently high dosages without resulting in liver injury (Walker et al., 1969). However, any stimulus or effect may be harmful if excessive (Hutterer et al., 1968; Street and Sharma, 1976). For example, 2 mg dieldrin/kg/day produced enlargement of liver, hypertrophy of SER and an increase in microsomal protein, P-450, and DMEs (the activity of DMEs per mole P-450 remained unchanged). The maximal level of induction was reached after 14 days, following which a new steady state was maintained. Rats treated for 28 days, though more tolerant to 5 mg dieldrin/kg than untreated ones, showed definite indications of decomposition of liver in response to the 5 mg dieldrin/kg dose. SER remained hypertrophied and microsomal protein and P-450 remained elevated but enzyme activity per mole P-450 decreased. Much of the excess SER formed tightly packed clusters of tubular membranes with no glycogen and little hyaloplasms, and some of the mitochondrial membranes were damaged. This phase of decompensation (hypertrophic but hypoactive SER) may serve as a criterion of toxic injury (Hutterer et al., 1968). Thus the threshold of injury may be marked by a decrease or a failure to increase activity in response to increased dosage. Phenobarbital and a few other compounds also produce morphological changes in the liver (Wright et al., 1972) and sufficiently high dosages of PB may lead to a phase of decomposition. 3-MC or BP cause little or no proliferation of SER (Mannering, 1972) while PB, Tolbutamide, nikethamide, and OCs cause marked changes (Hart and Fouts, 1965; Conney and Burns, 1972). 2. INDUCTION OF DME IN MAMMALS The so-called 'cytochrome P-450's of rat, rabbit, and mouse are different hemoproteins based on their inducibility by xenobiotics, catalysis, spectra, molecular weights, and immunological and electrophoretic characteristics (Tables 2, 3) (Levin et al., 1977; Coon et al., 1977; Fasco et al., 1978; Deutsch et al., 1978; Gibson and Schenkman, 1978; Guengerich, 1978). The nature of the induced DME reaction(s) depends on the type of

48

M . A . Q . KHAN

the cytochrome that is formed. In rats PB, 3-MC, and P C N (pregnenolone 16c~-carbonitrile) induce specifically BPA demethylase (also 7/?-hydroxylation of taurodesoxycholic acid), A H H (and 6/~-hydroxylation of taurodesoxycholic acid), and EM demethylase, respectively, along with the specific form of P-450" (Thomas et al., 1976: Powis et al., 1977). The apparently homogeneous forms of rat liver P-450, i.e. PB-inducible fractions B and D and 3-MC-inducible fraction B metabolize parathion at a similar rate (Guengerich, 1978). However, PB-inducible form D is specific for lasiocarpaine: PB-inducible form B metabolizes BPA, N,N-dimethyl nitrosamine, 2(N-ethylcarbamoyl hydroxymethyl)furan, and 4-ipomeanol; and 3-MC-inducible form B is specific for AHH, 7-ethoxycoumatin, N,N-dimethyl-4-aminoazobenzene, N-methyl-4-aminoazobenzene, and 4-ipomeanol (Guengerich, 1977a, 1977b, 1978). The differential induction of A H H (3-fold) (Burke et al., 1977) and ethoxyresorufin de-ethylase (150-fold) by 3-MC indicates that it may induce more than one form of P-448 (Bradshaw et al., 1978). The major PB-inducible form of rabbit liver P-450 (LM-2) is homogeneous (Haugen and Coon, 1976; Dean and Coon, 1977: Haugen et al., 1977). The beta-naphthoftavoneinduced P-450 (LM-4) of rabbit liver contains at least four distinct proteins (Haugen et al., 1977). The P-450LM-1 and LM-7 are inactive with warfarin, LM-2 and LM-3b have the same activities while LM-4 has a markedly different activity towards warfarin (Fasco et al., 1978, 1979). Forms LM-4 and LM-6 are both inhibited by BNF, but they are different proteins; the former preferentially metabolizes BP, the latter acetanilide (Jones et al., 1978; Johnson and Muler-Eberhard, 1977; N o r m a n et al., 1978). In mice, the induction of A H H and its associated P1-450 by P A H oxygenates BP in non-K region to eight different metabolites (controlled by locus Ah). Certain strains of mice such as D2 (Boobis et al., 1979) and guinea-pigs (Kawajiri et al., 1978) are resistant to PAHinduction. In mice PB induces four forms other than P-450 (Huang et al., 1976) which oxygenate BP in K-region (Boobis et al., 1979). Similar inductive effects on A H H have been observed in rats (Kinoshita et al., t973; Selkirk et al., 1974; Parke, 1977). In rats polychlorinated biphenyls,+ polybrominated biphenyls, and safrole may induce more than one form of P-450 (Table 5) (Bickers et al., 1974; Litterest et al., 1972, 1974; Ecobicon, 1976; Dent et al., 1970, 1976, Dent, 1978). Although P-450 from PB- or 3-MC-treated rats can exist in six forms (Thomas et al., 1976, 1978), at least three of these forms are catalytically active in Aroclor-1254-treated rats (Table 3) (Ryan et al., 1978). Forms a and b (high and low spin) have c o m m o n l y been recognized in rat (and rabbit) liver (and rabbit lung) microsomes (Comai and Gaylor, 1973; Bjorkham and Danielson, 1976; Mailman et al., 1974; Mull et al., 1975; Gustafsson and Ingleman-Sundberg, 1976; Wolf et al., 1978). These can be interconverted in vitro on addition:~ of substrates or detergents (Witmer et al., 1975) or ethyl isocyanide (Imai and Sato, 1966a), but more so by in vivo treatment of animals with inducers. Two soret peaks are formed by ethyl isocyanide at 430 and 455 nm; increasing the p H from 6 to 8, reduces the 430 and increases the 455 nm

*Ethanol-induced form preferentially catalyzes aniline hydroxylation and 7fl-hydroxylation of taurodesoxycholic acid (Comai and Gaylor, 1973; Hasumura et al., 1975; Bjorkhem et al., 1974', Ryan et al,, 1975: Gustafsson and Ingleman-Sundberg, 1976; Thomas et al., 1976; Levin et al., 1977; Lu and West, 1978; Dickins et al., 1978). tThe mixed effect on the induction of P-450 and P-448 is due to the specificity of PCB congeners to induce specific enzymes. The non-coplaner congeners, i.e. those with substituents in 2,2'- or 6,6'-positions appear to induce P-450 while the planer isomers (3,3'-) induce P-448 (Goldstein, 1979: Goldstein et al.. 1977: Poland and Glover, 1977). ~Flavones, especially, 7,8-benzoflavoneactivate BP metabolism by rat and human DME, when added in titro (Wiebel et al., 1971, 1974; Lu'and West, 1972; Selkirk el al., 1974; Sloane, 1965: Pelkonen et al., 1977: Kapitulnik et al., 1977). This markedly stimulates activation of aflotoxin B1 to mutagens in the case of human but not with rat DME (Buening et al., 1978). Millimolar concentration of alpha-naphthoflavone to liver microsomes can stimulate AHH activity of microsomes from control but inhibit in those from polyaromatictreated rats (Wiebel et al., 1971). This is because alpha-naphthoflavone stimulates P-450 and inhibits P-448 (Wiebel et al., 1975). In vitro addition of ethyl isocyanide and acetone activates aniline hydroxylation (Imai and Sato, 1966a; Anders, 1968); metapyrone activates acetanilide hydroxylation (Leibman, 1968). and certain carcinogens activate the 2-hydroxylation of biphenyl (McPherson et al., 1976).

Induction of drug-metabolizing enzymes

49

TABLE4. Effects o f C o m m o n Inducers of D M E on Insecticide Toxicity and M e t a b o l i s m Inducer Phenobarbital

Dosage

Species

Effect

50 mg/kg/day, ip

rat

50 mg/kg/day, ip

rat

25-30 mg/kg/day, ip

rat

50 mg/kg/day, ip

rat (also mice)

Hinosan antiche activity decreased (Chen et al., 1972) dieldrin storage in fat decreased (Cueto and Hayes, 1965) dieldrin excretion increased (Cook and Wilson, 1971) decreased toxicity of: parathion, malathion, demeton, disulfoton, azinphosmethyl, dioxathion, ethion, carbofenthion, mevinphos, EPN (Welch and Coon, 1964; DuBois and Kinoshita, 1965; Menzer and Best, 1968) increased elimination of BHC metabolites (Koranski et al., 1964) increased metabolism of DDT and DDE (Kinoshita and DuBois, 1970); hydroxylation of testosterone (Conney and Schneidman, 1964; Welch et al., 1967); and de-nitrification of 2-nitropropane (Ullrich et al., 1978) increased paraoxonase in liver, decreased in plasma/Welch and Coon, 1964) decreased toxicity of parathion, malathion, EPN (Welch and Coon, 1964) decreased dicoumarol toxicity (Welch et al., 1967) decreased Lindane toxicity (Earl et al., 1970) decreased insecticide residues (Street et al., 1966a; Street and Chadwick, 1967), increased dieldrin excretion (Cook and Wilson, 1971) decreased Warfarin action (Robinson and McDonald, 1968) increased griseofulvin absorption (oral) (Riegeleman et al., 1970) decreased PB sleep time, induced O- and N-Dem. and cyt-c-reductase (Stephen et al., 1971) slight increase in carbaryl excretion (Puyear and Paulson, 1972) increased cholesterol-7c~-hydrox (Hulcher et al., 1974) affected An. Hydrox, and AP-N-Dem (Sifri et al., 1973, 1975) increased N-dem of p-chl-N-methylan. (Gutman and Kirdon, 1971) decreased dieldrin storage in fat (Street et al., 1966a) decreased toxicity of dicoumarol (Dayton et al., 1961)

rat

r

rat

Phenobarbital

Phenobarbital (and cholestyramine)

Heptobarbital Heptabarbital

Phenylbutazone

100 mg/kg, i.p.

mouse

b.i.d, for 4 days

mouse

10 mg/kg for 10 days

dog

---

dog, swine cattle

2 mg/kg for 4 weeks

man

30 mg/kg for 3 days, t.i.d. i.p.

man quail

p.o.

quail

i.p.

pigeon

i.p.

chicken

76 mg/kg/day for 3 days 40 and 225 mg/kg/day

hen

in diet, 10 days 50 mg/kg, p.o. 400 mg/day, 4 days

dog, guinea-pig man man

50 mg/kg, 4 days, i.p.

rat

-

Tolbutamide Cyclazine Chlorcyclazine

J.P.T. 11/1

O

rat

-

60 and 290 mg/kg/day in diet, 10 days b.i.d., 4 days

-

rat

-

rat rat rat

25 35 mg/kg

mouse

25 mg/kg b.i.d., 4 days

mouse

50 mg/kg, i.p.

mouse

increased excretion of dicoumarol metabol. (Aggelar and O'Riley, 1969) dieldrin storage in fat unaffected (Sifri et al., 1975) induced testosterone hydrox (Conney and Schneidman, 1964; Welch et al., 1967) dieldrin storage in fat unaffected (Street et al., 1967) decreased toxicity of malathion, parathion, EPN, at high dosage increased mevinphos toxicity (Durham, 1967) decreased Schradan toxicity (McPhillips, 1965) decreased toxicity of Schradan, malathion, parathion, EPN (Welch and Coon, 1964; McPhillips, 1965) increased toxicity of parathion, EPN and their in vitro desulfuration (Welch and Coon, 1964; McPhillips, 1965) increased paroxonase in liver but decreased in plasma (Welch and Coon, 1964)

50

M. A. Q. KHAN TABLE 4 - continued

Inducer

Dosage

Species

Effect

rat

increased toxicity of azinphosmethyl (Murphy and DuBois, 1957, 1958) decreased PB effect (Durham, 1967) increased metabolism and storage of DDq. DDE tCranmer, 1970) increased toxicity of certain OPs (Kcplinger and Deichman, 19651 M F O induccd, increased parathion toxicity IGram, 1963~ increased azinphosmcthyl toxicity and hepatic antichE activity (Murphy and DuBois 1957, 1958) increased antichE activity of Hinosan {Chen et al,, 1972) decreased TOCP toxicity (Blciberg and Johnson. 1965~ induced M F O and P-450 [Powis et al., 1976: Kedo et al., 1977) induced P-450 and M F O Oames et al., 1977) decreased dieldrin storage in fat (Street et al., 1966a) decreased antichE activity of Hinosan (Chen et al., 19721 increased M F O activity towards EPN, DBD (Murphy and DuBois. 1958) and D M P in males and reverse effects in females inhibit D M P toxicity to female (Murphy and DuBois, 1958) decreased toxicity of Guthion and Schradan IMurphy and DuBois. 1958}, disrupted avoidance behavior by carbaryl and 3-isopropylphenyI-N-methylcarbamate (Goldberg et al., 1961) decreased toxicit) of Schradan, dimethoate, dimifex, mevinphos IO'Brien, 1967) increased paraoxonase in liver, decreased in plasma (Welch and Coon. 1964), decreased toxicity of EPN. malathion, parathion

Nikethimide

Diphenylhydantoin

250 ppm, 3--6 wks

rat

" + promazine

rat

Chlorpromazine

rat

3-methylcholanthrene

20 mg/kg

rat

5 mg/kg, i.p.

rat mice

20 mg/kg, i.p.

chicken

Aminopyrene

2 x 20 mg/kg, i.p. 75 mg/day, 10 days

fish rat

Testosterone

2 mg/kg i.p.

rat

Testosterone

rat

Steroids

-

rat

SKF-525A

rat

mouse 50 mg/kg, i.p.

mouse

TABLE 5. Characteristics of the Three Forms of Cytoehrome P-450 in Litter Microsomes ~[ Rat,s Pretreated with Arochlor-1254 (Ryan et al., 1977;)

1. Mol. Wt: x 103 2. Absorp max: nm 3. Substrate specificity: (i) Testosterone hydroxylation (ii) other specific reactions 4. Other specific inducers

Form A

Form B*

Form C**

47~48 452

51 52 450

55 56 447 or 448

7:t-

16:t BPA N demeth

PB, 3-MC

PB (major form)

hydrox of BP, zoxazolamine: 7-ethoxycoum. de-ethylation 3-MC (major form)

*This form is present to about 1 per cent in untreated rats (Miwa et al.. 1978). **In general this form is inhibited by adding alpha-naphthablavone in vitro. The in ~:ivo administration of latter stimulates P-450 (Wiebel et al., 1971, 1975).

Induction of drug-metabolizing enzymes

51

peak (Imai and Sato, 1966a). PB-treatment increases 430 and 455 nm peaks equally while 3-MC increases the 455 to a much greater extent than the 430 nm peak (Sladek and Mannering, 1966), the change in pH equilibrium between peaks is evident with 3-MC only (Imai and Sato, 1966b). n-Octylamine binding showed 3-MC to induce type a (maximum at 427 and minimum at 329 nm) and PB to induce type b (maximum at 432 and minimum at 410 nm) P-450, while uninduced microsomes showed an intermediate binding (Jeffcoate et al., 1969). Because of the EPR high spin heme signal and by analogy with the absorption spectra of alkaline and acid methemoglobins 3-MC induced P-448 is considered as high spin hemoprotein (Hildebrandt et al., 1969; Jeffcoate, et al., 1969; Witmer et al., 1975; Levin et al., 1974). In addition to 3-MC and PB induced forms, ethanol can induce a third form of P-450 (Comai and Gaylor, 1973; Hasumura et al., 1975). Organochlorine insecticides appear to cause inductive effects similar to those of barbiturates (metabolism of HB, AP, chloropromazine, acetophenatidin), however, because of their long life and storage in fat in animals the induction lasts for several weeks (Table 10) (Madhukar and Matsumura, 1979). The rate of synthesis of several enzymes increases very early after administration of the inducer. The inducers increase hepatic P-450 concentration, NADPH oxidase, and NADPH-cyt-c-reductase. Other increases are in: incorporation of 14C-acetate or 14C-mevalonate into cholesterol, 7~-hydroxylation of cholesterol; deiodination of thyroxin; demethylation of methylated purines, 6-dimethyl-aminopurine, and 6-methylaminopurine; and protein synthesis (Conney, 1967; Kuntzman, 1969). Stimulators of DMEs also stimulate hydroxylation of steroids (androgens, estrogens, progesterone, adrenocorticoids). Barbiturates enhance the glucuronidation of bilirubin (Catz and Yafee, 1962; Roberts and Plaa, 1967). PB causes both an increase in the rate of synthesis and a decrease in the rate of breakdown of NADPHcytochrome-c-reductase (Jick and Schuster, 1966; Kuriyama et al., 1969). 3. INDUCTION OF DME IN OTHER VERTEBRATES Inducers decrease barbiturate sleeping time in birds (Bitman et al., 1971) and induce DME (Powis et al., 1976; Kedo et al., 1977; Cecil et al., 1978). Induction of DME by drugs and carcinogens has been reported in several species of birds (Table 6) (Sell and Davison, 1973; Bend et al., 1974b; Pan et al., 1975; Abou-Donia, 1967; Kedo et al., 1977). Injection of polycyclic aromatic hydrocarbons and TCDD can increase the activity of several monoxygenase systems in marine fish, the Winter Flounder and the Little Skate (Bend et al., 1974a). 3-MC caused a 10-fold increase in P-450 content and AHH activity, and a 7-fold increase in 7-ethoxycoumarin deethylase activity in the sheepshead. The latter two enzymes were also inducible by dibenzanthracene in the Little Skate (Table 6) (James et al., 1977) where the increase was about 35-fold in the case of AHH (Bend et al., 1979). The induced cytochrome was P-448 as characterized on purification (Bend et al., 1979). Similar induction of several monoxygenase activities has been reported in the rainbow trout (Salmo gairdneri), brown trout (S. trutta), sculp (stenotomus versicolor), capelin (Mallotus villosus (Payne and May, 1979; Chevion et al., 1977; Statham et al., 1978; Addison et al., 1978). The barbiturate-type inducers seem to be ineffective in fish (Buhler and Rasmusson, 1968; Bend et al., 1979; Addison et al., 1977; Elcombe and Lech, 1979). In fresh water rainbow trout 3-MC injection induced AHH (Pederson et al., 1974) by 10 to 20-fold and P-450 by 1.5-fold with no effect on ethylisocyanide 455/430 nm ratio (Elcombe et al., 1979). Several other carcinogens induced P-450 in rainbow trout (Ahokas, 1979). Injection of Aroclor-1254, Aroclor-1242, and beta-naphthoftavone induced AHH, ethoxyresorufin and 7-ethoxycoumarin deethylation by 5 to 40-fold, but caused only 10-50 per cent increase in P-450 concentration in rainbow trout and changed the 455/430 ratio from 0.35 to 0.53 (Elcombe and Lech, 1978, 1979). The induced cytochrome (P-448?) had a molecular weight of 57,000 as compared with that of 53,000 for the induced rat liver P-448 by SDS-polyacrylamide gel electrophoresis (Elcombe and

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Lech, 1979). Beta-naphthoflavone injection showed only slight induction of epoxidation and hydroxylation reactions of the hepatic DME of the frog, Xenopus laecis (Dohcrty, 1978). That the exposure of the fish to chemicals in water can induce hepatic DME has also been reported. For example, crude oil induced AHH in brown trout, capelin (Payne, 1976), the killifish (Burns, 1976), and the striped mullet (Payne and May, 19791. Exposure of fish to OCs can cause pathological and functional changes in liver of Anguilla anguilla (Holmberg et al., 1972) and Labeo rohita (Konar, 1970). Chronic exposure to endrin caused hyperplasia of the islets of Langherans as well as altered the carbohydrate metabolism in cuthroat (Salmo clarki) while endrin injection (2.5 mg/kg) and exposure to 5 ppb endrin for 48 hr caused histopathological changes in the liver of Channa punctatus and Clarias leatrachus. DDT and related compounds and carbon tetrachloride caused similar changes in Heteropneustes jossilis (Mathur 1962; Sastry and Agarwal, 1975, Sastry and Sharma, 1978). 4. INDUCTION OF DME IN INVERTEBRATES Drug metabolizing enzymes have not been characterized thoroughly in citro in invertebrates (Khan et al., 1972) other than some insects (Wilkinson and Brattsten, 1972). This basic information is needed first before comparative studies on the DME can be validly evaluated. However, the exposure of marine invertebrates to crude oil in the medium has caused the induction of certain specific DME in a few species (Burns, 1976; Payne and May, 1979). Microsomal DME have been characterized in a terrestrial invertebrate, earthworm (Nakatsugawa and Nelson, 1972). Exposure of the earthworm, Pheretima posthuma to DDT, dieldrin and lindane has been shown to cause an increase in DDT metabolism in vit, o (Agarwal et al., 1978). In the protozoan, Tetrahymena pyriformis, addition of hexochlorobenzene to the medium at 0.1 ppm caused induction of activities of delta-ALA dehydratase, glutamate-oxaloacete transaminase, glutamic dehydrogenase, isocitric dehydrogenase, malic dehydrogenase, hexokinase and pyruvate kinase, while 1 ppm concentration of HCB depressed the activities of these enzymes (Geike, 1978). DME can be induced in some insect species by PB, 3-MC, OCs, OPs ecdysterone, and Juvenile Hormone analogues (Table 7) (Brattsten and Wilkinson, 1973: Hodgson, 1974). Houseflies are the most extensively studied insect species but almost all the work has been carried out with whole flies or their abdomens and not with particular organ(s). PB, butylated hydroxytoluene, triphenylphosphate induced DME and P-450 (Perry et al.. 1971) in several strains, while naphthalene induced in the Fc strain (Capdevile et al., 1973a, b; Stanton et al., 1979). PB induced metabolism of cyclodienes and their photoisomers in houseflies (Khan et al., 1969; 1970). Several strains resistant to oxidizable insecticides possess higher levels of DMEs (Tsukamoto and Casida, 1967; Schonbrod et al., 1968; Khan, 1969; Khan et al., 1973; Plapp, 1974) and higher levels of P-450 than susceptible or those strains which are resistant to insecticides not detoxified by DME. Several induced resistant strains possess P-448 while other resistant and susceptible strains possess P-450 and P-452. Uninduced Diazinon-R, Fc, and Dimethoate-R strains contain P-448 (Perry and Buckner, 1970: Philpot and Hodgson, 1971a: Tare et al., 1973). This differs from P-450 of susceptible strains in several respects: (a) the CO-maxima lie to the lower wave length, [b) type 1 binding is present, (c) type II binding is increased in relation to the CO spectra, and (d) ethyl isocyanide spectrum is changed in magnitude. P-450 of the Diazinon-R strain shifted to P-448 on treatment of flies with malathion, tropitol, MDG-264, and three substituted phenyl-2-propylether synergists. In the Fc strain with P-449, PB and naphthalene induced P-450 with lower CO-maxima, higher type I and type II ratios to the COmaximum, and a different ethylisocyanide equilibrium point than the untreated ones. This may resemble 3-MC induction in mammals (Tate et al., 1973: Capdevile et al., 1973a, b). P-450 of the Orhmdo-R strain is inducible by dieldrin (Matthews and Casida. 1970) but not by DDT (Tate et al., 1973) as evidenced by the ethylisocyanide spectra.

Induction of drug-metabolizing enzymes

55

Susceptibility of houseflies to insecticides can be influenced by diet (Perry and Buckner, 1970), e.g. flies fed on milk were more resistant than those fed on sugar and water to m-isopropyl N-methylcarbamate because of higher levels of DME and P-450. DME activity in gut of 35 species of caterpillars was significantly higher in polyphagous than in oligophagous ones and the activity in the latter group was significantly higher than in monophagous species (Wilkinson and Brattsten, 1972). The DME in caterpillar enables them to metabolize secondary plant substances in food and this enzyme capability has been adjusted by natural selection to the quality and quantity of these materials likely to be encountered. The extraordinarily high and generalized tolerance of the larval feeding stages of relatively polyphagous holometabolous insects to insecticides is probably the result of selection for endurance of prolonged and varied biochemical stresses associated with the diversity of the plants in their natural diet (Wilkinson and Brattsen, 1972). The feeding of the polyphagous caterpillars on plants shows no effect on gut DME. In insects the biochemical changes associated with metamorphosis (hormone regulated), different stages of development, and age can bring out large changes in enzyme activities including DME (Moriarty, 1969). In all species DME activity is greatest in actively feeding final instar larvae and declines during quiescence. In housefly there is a sudden burst of DME in last larval instar just before pupation which may be associated with the increasing ecdysone titers before pupation and low J.H. fl-ecdysterone stimulates DME in adult flies. A possible interrelationship exists between enzyme activity and the levels of insect hormones J.H. and ecdysone (Yu and Terriere, 1971) during development. An almost inverse relationship occurs with titers of ecdysone and DME in silk worm (Samia cynthia racini), being highest immediately before and during the molt and lowest during the midinstar. J.H., protein, and RNA syntheses are highest during the immediate postmolt and steadily decline as the instar progresses (Wilkinson and Brattsten, 1972). PB and 3-MC induced metabolism of DDT in Triatoma infestans (Morello, 1964; Agosin et al., 1969; Agosin, 1971) to polar metabolites which reduced DDT toxicity (which was overcome by SKF 525A) (Morello, 1964). In T. infestans nymphs DDT induced NAD-kinase which produces NADP through pentose shunt which is also induced and so was DME activity enhanced (Morello et al., 1971). In locust (Schistocerca gregaria) and southern army work (Spodoptera eridania) larvae PB and BP do not induce DME in fat body. In S. eridania larvae (Wilkinson and Brattsten, 1972) alkyl benzenes and other chemicals are good inducers of DME and P-450 in midgut (Brattsten and Wilkinson, 1973, 1977; Elshourbagy and Wilkinson, 1978). Caterpillars need much higher levels of inducers. Aroclor-1254 can induce AHH in gut microsomes; induction persists for four days after topical application (Anderson, 1978). In wax moth, PB and chlorcyclizine decreased toxicity of parathion, increased detoxication of EPN (several fold), and induced O-demethylation of PNA, and increased NADPH-NT-reductase in gut.

5. INDUCTION OF CYTOCHROME-C-REDUCTASE NADPH-cyt. c or cyt-P-450 reductase is increased on PB administration (Remmer and Merker, 1963; Orrenius and Ernster, 1967). It may be limiting the rate of overall DME activity (Gillette, 1969; Gram et al., 1968; Davies et al., 1969b). The reductase after daily PB treatment increased 4-fold (Schimke et al., 1968) and its half-life increased from 3 days in untreated to 3 to 4 days in PB treated rats indicating that it is due to its reduced degradation (Jick and Shuster, 1966, Kuriyama et al., 1969). The rate of benzphetamine N-demethylation by purified P-450 of rats treated with PB is increased by addition of reductase (Miwa et al., 1978). However, reductase from PB- or 3-MC rats did not confer any specificity of the purified P-450. Cytochrome P-448 and reductase from PB-treated rats metabolized BP at 20-times higher rate than P-450 and reductase from 3 MC-treated

56

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rats. Benzphetamine N-demethylase activity must, therefore, reside with P-450 (Lu et al., 1972). The most potent inducer of P-448 type monooxygenase T C D D is also about 17,000 times more potent inducer of DT-diaphosase of rat liver (Beatty and Neal, 1976). 6. I N D U C T I O N O F H E M E SYNTHESIS Several polyhalogenated aromatic and aliphatic compounds are known to interfere with heme synthesis. Some of these cause porphyria in humans, experimental animals and wildlife. These include hexachlorobenzene, PCBs, PBBs, chlorodibenzo-p-dioxins, methylchloride, and vinylchloride (Steik, 1979). Delta-ALA synthetase (ALAS1 activity in liver mitochrondria, which is the rate limiting enzyme of heme synthesis, is increased 40-100 times by certain compounds (DeMatteis, 1967). The de novo synthesis of ALAS is thought to resemble the induction of DMEs in four ways (a) the response has so far been observed in liver, (b) a chemical may induce more than one enzyme activity (c) the induction is not hormonal, (d) the induction does not occur rapidly in dividing liver cells (DeMatteis, 1967; Hayes, 1975: Stephens et al., 1978). ALAS can be induced by a variety of chemicals including some that induce DMEs. However, it seems that chemicals that induce ALAS efficiently are poor inducers of DMEs and vice versa (Granick, 1975). Occurrence of two kinds of induction is illustrated by the action of the pesticide, m-dichlorobenzene in rats. Following daily dosages at 0.89 g/kg, there is a biphasic stimulation of ALAS activity and the secretion of urinary coproporphyrin, both of which peak by 3 days and then decline; the decrease at 5 days corresponds with maximal stimulation of drug metabolism and with a decrease in the concentration of m-dichlorobenzene in the serum and the liver (Poland et al., 1971). Hexachlorobenzene induces hepatic ALAS (Granick, 1967; Rajamanickam et al., 1972) and has been shown to disturb porphyrin metabolism in human (Ockner and Schmid, 1961 ; DeMatteis et al., 1961; Cam et al., 1963; Vos et al., 1971). T C D D is one of the most potent inducers of heine synthesis in humans, other mammals and chickens (Poland and Glover, 1974, 1977). In the chick embryo, out of the 15 halogenated dibenzo-p-dioxins tested, only 5 isomers which had at least 3 of the 2,3,7,8-positions halogenated with one of the free carbon were inducers of ALAS (Poland and Glover, 1974, 1977). The mitochondrial ALAS is the rate-limiting step in heme biosynthesis. It has a short life of 60 to 90 minutes and its induction and repression may be significant to the changed activities of DMEs. A rapid increase in ALAS within several hours after PB treatment provides additional heme for the drug-induced increases of microsomal cytochromes. PB stimulates synthesis of microsomal hemoproteins as measured by Fe 59 incorporation, or by glycine or ALA incorporation into microsomal fractions containing hemoproteins; the addition of heme largely prevents increases in synthesis of P-450, phospholipid, NADPH-cytochrome-c-reductase. AP-N-demethylase and HB oxidase (Gelboin, 1972). There was no effect of PB or 3-MC on the incorporation of ALA into CO-binding cytochrome, but the rate of loss of radioactivity from these microsomes was decreased by 3-MC which induces a new cytochrome (P-448). Since hematin is a known repressor of heine synthesis, the heme synthesis may play an important role in the induction of DMEs. The receptor site for the inducer may be microsomal hemoprotein and hematin may compete with the inducer for these sites. Although heme synthesis is required for induction of microsomal cytochrome, it is not clear whether heme synthesis is also necessary for the early (one hr in tissue culture, and 4--5 hr in vivo) larger rises in DMEs and if the regulatory role of ALAS is initial or concomitant to increases in microsomal cytochromes (Mannering, 1972). In liver cells, heme synthesis is not controlled by the allosteric inhibition of ALAS but rather by a repressor mechanism that controls the synthesis of ALAS. The repressor mechanism consists of a repressor protein (heme being co-repressor) which acts to block an operator gene, thus blocking the formation of m-RNA that can be translated into the polypeptide ALAS. There should be competition between heme and the inducer for the

Induction of drug-metabolizing enzymes

59

active site on aporepressor. If the chemical displaced the heme, the repressor action would be blocked and as a consequence more ALAS would be synthesized and more polypeptide formed. The porphyrin-inducing activity of the inducer should be prevented by heme (Granick, 1965). Fluoroxene (2,2,2-trifluorethyl vinyl ether) and allyl-iso-propyl-acetamide (AIA) which inhibit ALAS seem to have slightly different effects on P-450 and P-448. ALA reduced heme synthesis and thus degradation of PB-inducible P-450 (it also reduced heme and aniline binding and PNA-demethylase, but had no effect on EM demethylase, AHH and ethoxyresorufin deethylase) in rat liver. Fluoroxene preferentially degraded 3-MCinduced P-448 (Bradshaw et al., 1978). Barbiturates induce heme synthesis in chickens (Granick, 1965; Strittmatter and Umberger, 1969; Kedo et al., 1977) and pigeons (Kedo et al., 1977). Foreign chemicals (OCs) can also induce heme synthesis in houseflies (Plapp, 1974).

7. MECHANISMS OF INDUCTION OF CYTOCHROME P-450 As we have seen the exposure of animals to inducers of DME, whether occasional or continuous, may alter the homeostatic mechanisms for steady-state maintenance (synthesis, degradation, etc.) of morphological and functional entities of microsomes of the cells of the particular organ in genetically responsive animals (Conney and Gilman, 1963 ; Conney, 1967; Renton and Mannering, 1977). This alteration may (as in the case of PB) or may not (as in the case of PAH carcinogens) remain under homeostatic control. In the case of the liver, the hypertrophy and the growth of ER which occurs on repeated administration of inducers may involve different processes (Schulte-Herman, 1977a, 1974; Conney and Gilman, 1963; Kato et al., 1964). The gross protein synthesis which parallels the increase in DME activity in early stages of induction probably comprises changes in the rates of synthesis of many proteins (Decken and Hultin, 1960; Gelboin and Sokoloff, 1964a, 1964b; Kato et al., 1964b). Since microsomal enzymes amount to a relatively small number of total cell proteins, even marked changes in their rates of synthesis could not account for the gross changes in protein synthesis. Genetics of the expression of the semidominant gene(s) that control P-450 synthesis (and associated DME reactions) have been studied in mice (Haugen et al., 1976) and houseflies (Khan, 1969; Khan et al., 1973). The sequence of molecular mechanisms involved in the expression of this gene, from the activation of the genome until the catalysis by the newly synthesized P-450 system (heme + apoprotein and P-450 reductase), have been studied by investigating the effects of inducers of DME (PAH, PB, OCs) and inhibitors of transcription and translation in some mammals (Nebert and Gelboin, 1968; Bresnick and Madix, 1968; Arias et al., 1969a, Omura et al., 1969; Morello, 1965) and insects (Morello et al., 1971; Agosin et al., 1966; Agosin, 1971; Khan and Matsumura, 1972; Yu and Terriere, 1972, 1973; Elshourbagy and Wilkinson, 1978). The initiation of the process of induction of DME by PB or 3-MC which takes place within an hour after their injection in rats or mice may involve (i) increased synthesis of the same protein (ii) synthesis of a new protein, (iii) stabilization of the pre-existing protein by preventing its degradation. The approximate mean half-life of microsomal proteins and hemoproteins is estimated to be, respectively, 2 to 2.5 days (Arias et al., 1969a) and 2-50 hr (Maines, 1977). The mean half-life of P-450, the most abundant of cytoplasmic hemoprotein is biphasic ranging from 7 to 16 hrs (Maines, 1977). There is significant heterogeneity of turnover rates of different proteins (Arias et al., 1969a). The induction of the microsomal P-450 reductase in rat liver by a single PB injection may be due to the increase as well as the blockade of the degradation of the same enzyme (Omura et al., 1969). The induction reached a maximum of 300-400 per cent above the normal rate at around 5 hrs after PB injection. The induction effect of PB on reductase may be at the translation level (Omura et al., 1969).

60

M . A . O . KHAN

The induction of P-450s or P-448s involves synthesis of new cytochromes (Nebert and Gelboin, 1968; Bresnick and Madix, 1968). The synthesis of new cytochrome P-448 by PAH and other 3-MC-type inducers involves modification(s) at the transcription (Gielen et al., 1972: Goujon et al., 1972: Bresnick and Nosse, 1969), translation (Lanclos and Bresnick, 1976: Nebert and Gelboin, 1968) and post-translation levels (Kaht et al., 1977. 1978; Maines, 1977). 3-MC causes an increase in the aggregate RNA-polymerase in liver nuclei (Bresnick et al., 1968: Nebert and Gelboin, 1968; Gelboin et al., 1967) by activating the genome (chromatin). The chromatins from 3-MC-induced cells did not differ from those of the controls, except for the increase in action of RNA-polymerase. However, the RNA synthesized differed from that of control rats (Bresnick and Madix, 1968: Bresnick and Mosse, 1969). BA appeared to operate at the translation level of the m-RNA (Nebert and Gelboin, 1968). A cytosolic repressor (apoprotein) may combine with 3-MC or BA, and the active depressor (whose synthesis may be blocked by high levels of PAH or Actinomycin D (Actinomycin D blocks 3-MC and/or TCDD-induced synthesis of AHH [Gelboin, et al., 1967: Beatty and Neal, 197611 may interact with the genome at the region(s) responsible for the elaboration of specific m-RNA (Nebert and Gelboin, 1968; Bresnick and Madix, 1968). PB also induces RNA-polymerase possibly by combining with a repressor in the cytosol which may regulate the nuclear mechanisms leading to RNA and protein synthesis; but the mechanism(s) may be different than the ones involved with 3-MC (Gelboin et al., 1967: Bresnick, 1966). PB had a small but significant effect at the ribosomal level (Seifert et al., 1968; Omura et al., 19691. That the metabolites of BP can co-valently bind to DNA in citro in microsomes of cell culture and mouse liver (Boobis et al., 1979) indicate that if transported from microsomes to the nucleus the active metabolites of inducers may also act directly on the genome. In rats, there is an increase in the rate of mitosis and in the number of nuclei with a corresponding acceleration of 3H-thymidine incorporation in DNA using c~-hexachlorocyclohexane as an inducer (Schulte-Hermann et al., 1976). DDT also induces RNA synthesis indicating its action at transcriptional level for four different renal enzymes (Kacew et al., 1972), but at translational level for DME (Conaway et al., 1977). To summarize, inducers have profound effects on: hepatic nuclei (Schulte-Hermann, 1977b), increased incorporation of orotic acid and thymidine into nuclear DNA (SchulteHermann, 1977a) and RNA, increased RNA/DNA ratio in the nucleus, increased m-RNA in nucleus, stimulation of RNA-polymerase in the nucleus (Gelboin and Sokoloff~ 1964a), increase in enzyme protein and activity in microsomes, increased incorporation of amino acids into m-RNA in microsomes, and increased sensitivity of added m-RNA in microsomes (Gelboin, 1964: Kato, 1966: Kato et al., 19691. These effects are blocked by actinomycin-D (which inhibits DNA-dependent RNA-polymerasel, puromycin (inhibits protein synthesis in microsomes by preventing the transfer of s-RNA-bound amino acids into polypeptide), ethionine (blocks protein synthesis at several different levels by trapping ATP as S-adenosylmethionine). In resistant houseflies, DDT caused increased incorporation of amino acids into total proteins (Agosin et al., 1966) and in polysomal (Ishaaya and Chefurka. 1971) and microsomal proteins (Agosin et al., 1966: Ishaaya and Chefurka, 1971). Preceding this there was increased incorporation of bases into RNA (Agosin, 1971; Balazs and Agosin, 1968: Litvak et al., 1968). m-RNA from induced flies had 7-fold higher template activity for protein synthesis (Litvak et al., 1968: Balazs and Agosin, 1968). DDT seems to act on nuclear material, chromatin or polymerase and may have a direct effect on DNAdependent RNA-polymerase which becomes induced prior to m-RNA and protein synthesis. Actinomycin-D blocks dieldrin induction of MFO (Yu and Terriere, 1971) and DDT-induced uracil incorporation into RNA (Balazs and Agosin, 1968). This material has no effect on leucine incorporation into membranes following DDT treatment (Ishaaya and Chefurka, 1971). Puromycin (releases peptides from RNA-ribosome complexes) had no effect on dieldrin induction (Litvak and Agosin, 1968), while cyclohexamide blocked dieldrin-induced MFO activity and protein synthesis (Walker and Terriere, 1970).

Induction of drug-metabolizing enzymes

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DDT induces protein synthesis and RNA synthesis in T r i a t o m a infestaus (Agosin et al., 1965) and in the fat body of the American cockroach (Khan and Matsumura, 1972). Dieldrin seems to be similar to DDT in such effects in the cockroach (Khan and Matsumura, 1972). The role of some known active metabolites of xenobiotics formed by DME in carcinogenicity and enzyme induction is an area that needs extensive investigations. In mice, PB induces forms other than P1-450 which oxygenates BP in K region while 3-MC induces P-450 which oxygenates it in non-K region. The balance between the ratios of each form of P-450 to its other forms along with that of epoxide hydratase can influence markedly the quantity and quality of reactive intermediates of BP to bind to DNA (Boobis et al., 1979). Similar effects of these inducers on the metabolism of BP have also been observed in rats (Selkirk et al., 1974). In rats, activation of biphenyl-2 hydroxylation by 3-MC, BP, and safrole leads to metabolic activation of the carcinogen with the formation of a highly reactive metabolite which, in addition to alkylating the nuclear DNA, also causes the switch of the cell metabolism to the foetal state of rapid cell growth and cell division. The latter may potentiate the damage to DNA leading to malignant formation (Parke, 1977). Feeding of 0.5 per cent ethoxyquin to rats did not affect AHH but increased, by 3-fold the catalysis by liver microsomes of the formation of benzpyrene-7,8-diol-9,10-epoxideDNA nucleo-side adduct (Kahl et al., 1978; Kahl and Netter, 1977; Parke et al., 1974a, b). Addition of UDP-glucuronic acid in vitro to microsomes conjugates quinone and phenol metabolites of BP, stimulates BP metabolism, and increases (2 to 7-fold) benzpyrene-7,8-dihydrodiol-9,10-oxide-DNA complex (Fahl et al., 1978). Formation of BP-dihydrodiol-oxides requires a sequence of oxidations at cytochrome P-450, hydration at epoxide hydratase followed by a further cytochrome P-450-dependent oxidation of dihydrodiol. The complex of BP phenols and dihydrodiols with UDPGA in microsomes removes product inhibition of BP metabolism. Further hydrolysis of these conjugates by beta-glucuronidase may lead to complexing with DNA (Fahl et al., 1978). Induction of the U D P G transferase (Lake et al., 1978) and hydrolysis (glucuronidase) of this conjugate can thus facilitate complexing with DNA. Similar modifications of BP metabolism may be tested for mutagenicity (Razzouk et al., 1978). Similar activation of other PAH, biphenyls, PCBs, cyclodiene insecticides, DDT, methoxychlor, etc. by DME may be responsible for their inductive, carcinogenic, mutagenic, and esterogenic effects. 8. INDUCTION OF DME WITH INSECTICIDES 8.1. CHLORINATEDHYDROCARBONS(OCs)

OCs are among the most potent, long lasting inducers of DMEs of mammals and other animals. The induction which affects the metabolism, storage, and excretion of xenobiotics may influence the acute toxicological and pharmacologic action of other pesticides, environmental contaminants and drugs. For example, rats treated with DDT (Table 9) or chlordane (Table 10) show induction of DMEs (also seen with DDE, DDD, heptachlor, and chlordane) (Hart et al., 1963; Hart and Fouts, 1965; Mullen et al., 1966; Remmer et al., 1968, 1969; Bunyan et al., 1971; Lucier et al., 1972; Madhukar and Matsumura, 1979) and a decrease in barbiturate sleeping time (Conney et al., 1967), protection from gastric lesions of phenylbutazone (Welch and Harrison, 1966) and from toxic action of Warfarin (Ikeda et al., 1968; Burns, 1969), a decrease in storage and metabolism of dieldrin (Street, 1969a) and lindane (Chadwick and Freal, 1972), and an increase in the metabolism of steroids (Kuntzman et al., 1964; Conney et al., 1967). The most recent and excellent report of induction and inhibition of various reactions of DME in rats is that of Madhukar and Matsumura (1979). There appears to be an orderly dosage and DME induction response relationship, in the case of DDT, toxaphene (Kinoshita et al., 1966; Gillett 1968; Hoffman et al., 1970), TCDD (Poland and Glover, 1974, 1977) and other compounds (Hoffman et al., 1968;

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Induction of drug-metabolizing enzymes

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Gielen and Nebert, 1971). However, since some of the metabolites of the OCs (for example DDE from DDT, oxychlordane from chlordane, photodieldrin ketone from photodieldrin) are more lipophilic and liable to be stored in the body, the cumulative affects of the parent OC and these metabolites on the induction of DMEs should be investigated before accepting such conclusions. The threshold dosage for enzyme induction corresponds to the upper limit of intake that can be metabolized by the un-induced liver (Hoffman et al., 1970). The threshold dosage (mg/kg/day) varies anywhere from 0.05 (equivalent to about 1 ppm in diet) (Kinoshita et al., 1966; Street et al., 1966b) to 0.5 mg/ kg/day (Schwabe and Wending, 1967; Gillett, 1968; Datta and Nelson, 1968) depending on experimental designs. Intraperitoneal injection of DDT to rats at 1 mg or 2 mg/kg resulted, in 9 and 4 ppm or 15 and 5 ppm DDT in fat, respectively, causing 25 per cent and 50 per cent reduction in PB hypnosis (Gerboth and Schwabe, 1964). A dosage of 0.2 mg DDT/kg/day for 20 weeks resulted in a storage of 39 and 76 ppm in adipose tissue of male and female rats, respectively; and 12 weeks after the termination of DDT feeding the levels of DDT-related materials fell to 11 and 21 ppm, as compared to 6 and 9 ppm, respectively, in controls (Datta and Nelson, 1968). Prolonged feeding (for 3 months) of DDT at 5 ppm in diet showed 10 ppm of DDT and related materials in fat, induced DMEs, and reduced PB-sleeping time (Table 9). The metabolism of HB and AP remained elevated (Hart and Fouts, 1965). One ppm DDT in the diet can cause such effects also, and this is the acceptable limit in food according to FDA guidelines (Kinoshita et al., 1966). Induction resulting from a dosage of 200 mg of DDT/kg persisted for 90 days (with dieldrin it persisted for only 20 days). DDE seems to be more effective than DDT (Bunyan et al., 1972). TCDD, (2,3,7,8-tetrachlorodibenzo-p-dioxin) one of the most toxic, persistent, and potent inducers, is about 30,000 times more effective than 3-MC as an inducer of DME in rat. A single dose of 1 #g/kg can cause induction that can persist for about 35 days (Poland and Glover, 1974). Mirex (Baker et al., 1972) and photoheptachlor (unpublished data, this laboratory) seem to be next to TCDD in having very low threshold and cause much greater induction of DMEs and P-450 (6-fold) at high dosages. Threshold dosage for toxaphene is 5 ppm (Kinoshita et al., 1966), however, only a slight dosage-induction relationship is evident with chlordanes (Hart and Fouts, 1963, 1965). In rats, DDT causing increase in liver weight and proliferation of ER, showed induction of DMEs (Street, 1969b; Hoffman et al., 1970 Morello, 1965), reduced PB hypnosis (Bitman et al., 1971), and increased metabolism of steroids (Kuntzman et al., 1964). D D D (subcutaneous and oral) stimulated synthesis of hepatic enzymes which affected the metabolism and hypnosis of PB (Straw et al., 1965). In female rats dieldrin storage in fat was depressed by DDT (Street, 1968), AP, tolbutamide, phenylbutazone, heptabarbital (Street et al., 1966). DDT, DDD, DDE, and Kelthane feeding induces DMEs (Hart and Fouts, 1963; Straw et al., 1965; Gillette et al., 1966) with DDE being the stronger inducer (Bunyan et al., 1971). DDT (but not dieldrin) increased carcinogenicity of N-2 fluorenylacetamide (Weisburger et al., 1965). DDT synergized 1,l-his (p-chlorophenyl)-ethanol (Durham, 1965a). A single dose of DDT caused AP-N-demethylase and HB-oxidase to remain higher even after P-450 returned to normal levels (Remmer et al., 1968). DDT induced HB metabolism in rats but not in mice (Fouts, 1970a, 1970b) while chlordane stimulated in both. Rats with 10 ppm DDT and DDE in body fat (following injection of 1 mg DDT/kg) showed increased metabolism of PB and these levels may be common in humans in certain countries (Durham, 1965b; Quinby et al., 1965). Other commonly used OCs (methoxychlor, chlordane, heptachlor, aldrin, dieldrin, endrin, lindane) increase DME activity which metabolize HB, AP, chlorpromazine, bishydroxycoumarin, and decrease action of HB (Tables 1, 2 and 9) and Warfarin (by 10-fold). Stimulatory effects last for several weeks after cessation of exposure presumably due to their prolonged storage in body fat. A single i.p. injection of 40 mg dieldrin or 200 mg DDT/kg resulted in a gradual elevation of acetophenatidin and HB metabolism (in vitro) returned to normal by 90 days and 20 days in the case of DDT and dieldrin, respectively.

70

M . A . Q . KHAN

Chlordane has delayed and long-lasting action, it induces metabolism im ritrol of H B. AP, and chlorpromazine, which is inhibited by ethionine (Hart et al., 1963: Hart and Fouts, 1965). A two-fold increase in P-450 by chlordane feeding is greater than that seen with 3-MC but less than that seen with PB. Chlordane increases zoxazolamine hydroxylation more than that seen with 3-MC or BP. However, AHH and NADPH oxidase are similarly induced by all three inducers (Mullen et al., 1966). Endrin reduced hexobarbital sleep in male rats (Hart et at., 1963; Khan et al., 1979), but depressed hepatic P-450 in female guinea-pigs (Pawar and Kachole, 1978). Repeated doses of DDT and lindane increased oxidative hydrolysis, O-demethylase. dehydrochlorinase, and glucuronyltransferase, but to different degrees (Chadwick et al., 1971); metabolism of a single dose of lindane was increased by 2.5- and 5-times over the controls. DDT pretreatment produced more neutral and weakly polar but less free acid-type metabolites of lindane; so the two inducers caused qualitatively and quantitatively different effects. Rats pretreated with DDT plus lindane excreted more 2, 4, 5-trichloro- and 2, 3, 4, 6- and 2, 3, 4, 5-tetrachlorophenols by the second day of treatment than did lindane treatment alone (Chadwick and Freal, 1972), so DDT had selective effect on induction leading to the formation of 2, 3, 4, 5-tetrachlorophenol. Thus when two inducers are involved, the resulting induction may be additive (e.g., PB or DDT with polycyclic aromatic hydrycarbons) or slightly antagonistic (PB plus DDT or polycyclics plus polycyclic hydrocarbons) (Gielen and Nebert, 1971). The induction of DMEs following a single dose of HCH persists for 14, 28, and 56 days with ~-, [~-, and ~,-isomers, respectively (Koransky et al., 1964); rats become refractory to rodenticides, silicoside and red squill which can be prevented by ethionine and CFT 1201 (Koransky et al., 1964). HCH protected against convulsive effects of cardiazole (Herken et al., 1952: Ghazal, 1964). Alpha isomer is the most potent inducer of DME (Schulte-Hermann, 1977a). Oral treatment of dogs with DDT or chlordane (5 mg/kg, 3 times a week for 5 to 6 weeks) enhanced metabolism of AP, bishydroxycoumarin and phenylbutazone, some effects were evident even 4 months after the termination of treatment (Burns et al., 1965: Conney et al., 1967; Welch et al., 1967; Burns 1969). DDT and DDD have been reported to prolong barbiturate hypnosis (Nelson and Woodward, 1949: Nichols et al., 1958: Azarnoff et al., 1966). A 5 mg DDT/kg/day dose for 2 weeks increased liver weight in squirrel monkeys (Chadwick et al., 1971) and induced DME by 2- to 6-fold (Gram and Fouts, 1967, 1969), while 0.5 mg DDT/kg/day (intraperitoneal) for 2 months increased O-demethylase by 3-fold (Cranmer, 1970). Chlordane caused a 5-fold increase in P-450 in squirrel monkey and this was greater than the simultaneous induction of DME (Gram et a l , 1967; Cranmer et al., 1972). Feeding 1 ppm dieldrin and heptachlor to rats (also to swine and sheep) induced DMEs (Kinoshita et al.. 1966; Hoffman et al., 1970: Vanio, 1974). In mice, DDT prolongs barbiturate hypnosis (Hart and Fouts. 1965: Grady et al., 1965) which is followed by a reduction in sleeping time (Gabliks and Maltby-Askari, 1970). Single doses of chlordane, Trichlor-237, and endrin affected barbiturate hypnosis, but DDT had no effect (Hart and Fouts, 1963). DDT, DDE, and Mirex induced P-450 in mice (Abernathy et at., 1971 ; Chabra and Fouts, 1973), and other mammals (Bunyan et al., 1972; Baker et al., 1972; Bunyan and Page, 1973~. Pretreatment with DDT, PB, or BP did not alter the ethylisocyanide-P-450 difference spectrum in the North Carolina Board of Health strain of mice, or by Mirex of other mouse strains suggesting that similar types of P-450 was induced (Abernathy et at., 1971; Baker et al., 1972). However, Mirexinduced microsomes showed P-450/benzphetamine type I and/pyridine type [1 ratios to differ from those of untreated mice. Chlordane induces DME in rat, rabbit, mouse, dog, and squirrel monkey. A very extensive study on effects of various pesticides on rat hepatic DMEs has been undertaken by Madhukar and Matsumura (19791. The data has been summarized in Tables 9, 10 and 11. Induction or inhibition of P-450 has been checked employing ethylisocyanide spectra to show which peak is being affected and the resulting effect on various catalytic reactions can then be explained. The significance of alterations in drug or pesticide action in man is extremely difficult to assess (Madhukar and Matsumura, 1979). The threshold dosage of DDT in rats is

Induction of drug-metabolizing enzymes

71

0.05 mg/kg/day equivalent to 1 ppm in diet. This dosage is only 0.2 times that known to be effective in man (Laws et al., 1967; Poland et al., 1970) and is 50-times greater than the average dietary intake of all DDT-related OCs by a 16-19 year old man which is 0.9 mg/kg/day (Duggan and Lipscombe, 1969). However, FDA has allowed 1 ppm DDT in food and this daily intake in rats can produce body levels of DDT and its metabolites which are common in humans (Durham, 1965a, b; Quinby et al., 1965) and stimulate DMEs. In people occupationally exposed to DDT the serum half-life of phenylbutazone is about 20 per cent lower than in the control population (Kolmodin et al., 1969; Conney et al., 1971). Workers in a pesticide factory exposed to DDT and lindane metabolized AP twice as rapidly and DDT in their fat was 20-30 times higher than in controls. Half-life of phenylbutazone decreased and urinary excretion of 6fl-hydroxycortisol increased. Drugs that induce DMEs increase metabolism and excretion of the stored cyclodienes. In cattle (sheep, cows, goats, calf, pig) these inducers (25 or 30 mg P,B/kg for 5 days) lower insecticide residues. In bulls and rats PB increased urinary excretion of stored DDT in form of DDA; in rats it increased in vitro metabolism of DDT to DDD. In rats, PB, tolbutamide, heptabarbital, phenylbutazone and methoxychlor depress dieldrin and HCH residues. In man, PB, diphenylhydantoin or a mixture of anticonvulsants lowered DDE in blood (Davies et al., 1969a). OCs induce DME hydroxylation of steroid hormones (increased metabolism and excretion) which may alter normal body metabolism in mammals (Kuntzman et al., 1965; Conney et al., 1967, 1971; Conney, 1972) and man (Conney et al., 1971). OCs either stimulate or inhibit microsomal testosterone hydroxylation depending on whether they are administered chronically or acutely (Welch et al., 1967). The steroid induction probably occurs in response to relatively high inducer concentration and is balanced by an increase in the rate of biosynthesis in the appropriate endocrine gland. Metabolites of OCs can be more potent inducers and inhibitors as has been reported for DDE and DDD (Kupfer and Bulger, 1976; Kupfer, 1975). In the case of methoxychlor, its di-demethylated metabolite, 2,2-his (para-hydroxyphenyl)-l,l,l-trichloroethane, inhibits the binding of estradiol-17B to uterine cytosolic estrogen receptors in rats (Bulger et al., 1978). In rats dietary intake of DDT at 150 ppm for 21 days induced DME activity to an extent more closely related to tissue levels of DDT (Bunyan et al., 1972). In humans, changes in DME activity do not correlate with serum DDT (Poland et al., 1970). Oral administration of DDT (5 mg/kg) to squirrel monkey induced DME maximally after 8 days (Cranmer et al., 1972). Intraperitoneal injection (5 mg DDT/kg per day) showed maximum induction in only 7 days (Juchau and Fouts, 1966). Baboon and rats, when fed DDT orally (at 5, 15, 50 mg/kg per day) showed induction after 4 days. DME induction after 21 days and induction of glucuronidase after 18 days were dose related. Induction of P-450, O-demethylase, N-demethylase, aniline hydroxylase and p-nitrobenzoic reductase showed similar patterns in both mammals (Down and Chasseaud, 1978). In rats, polychlorinated biphenyls induce hepatic microsomal protein synthesis (Turner and Green, 1974) and DME (Goldstein et al., 1975, Goldstein, 1979; Narbonne et al., 1978) along with the enlargement of liver and proliferation of endoplasmic reticulum (Allen, 1975; Kasza et al., 1976; Krampl and Kontsekova, 1978). PCBs also alter lipid metabolism (Nagai et al., 1971). As in the case of DDT, methoxychlor, and olefinic cyclodienes, activated intermediate metabolites of PCBs may be responsible for chronic liver injury (Seymour et al., 1976). In male rats out of 20 pure isomers only 2,4,5,2',4',5'- and 2,3,4,2',4',5'-hexachlorobiphenyls induced both 3-MC- (cytochrome P-448; AHH activity, zoxazolamine metabolism) and PB-type (liver weight, microsomal protein, cytochromes b5 and P-450, N-demethylation of benzphetamine and HB metabolism) inductions (Alvares, 1977). PCBs had a marked stimulatory effect on AHH activity in lung, kidney, and intestine of rats. Induction of the hepatic DME in gestation is, however, primarily of the 3-MC-type (Alvares, 1977). Small residues of OCs and other inducers occur in human and other animals (Duggan and Lipscombe, 1969) as a result of food, water, and air intake. Such levels may be high

72

M . A . Q . KHAN

in certain environments, especially due to occupational exposures. Human tissue residues will persist for some time in view of the continued presence of traces of the OCs in the environment. The potential human hazard posed by these residues and their possible interactions with drugs (Poland et al., 1970; Kay, 1974; Hunter and Neal, 19741, insecticides (Adamovic et al., 1978); and other environmental agents are open to question. It is possible that apparently invisible cumulative effects of OCs and other inducers in the United States population may be serious in certain areas, under certain environmental conditions, especially in certain humans. Because of their generally low mammalian toxicity, there is only a remote possibility of interactions occurring to enhance acute toxicity of the OCs per se. Consequently, interactions affecting tissue storage levels and with the possible consequences of these residues on the biological activity of other types of chemicals needs to be investigated. Chlorinated hydrocarbons have been regarded to cause drastic effects on eggshell thinning of several reptorial birds. OCs can increase liver size and weight in several birds (Gillett, 1968; Khan et al., 1977). However, the reports on the alteration of DME have not provided clear-cut information mainly because enzyme activities by most workers have been determined at mammalian optima at which the activities are only about 25 per cent of those seen at avian optima (Runnels and Khan, 1974: Grossman and Khan, 1979). DDT induced heptachlor epoxidase activity in Japanese Quail (Gillett et al., 1966). Induction is related with the tissue levels of DDT and not with the dosage (Bunyan et al., 1972). D D M U also induced aniline hydroxylase (Bunyan and Page, 1973: Bunyan et al., 1972). However, the newly hatched quails produced from eggs laid by females fed DDT showed a decrease aniline hydroxylase activity (Sell et al., 1971, 1972). In adults. DDE (150 ppm for 21 days) also reduced the activity of this enzyme. DDT feeding reduced aniline hydroxylase but not P-450 or N-demethylase in white leghorn (Sell et al., 1971, 1972; Cecil et al., 1978). However, DDT feeding induced aniline hydroxylase in laying mallard duck without affecting AP N-demethylase and P-450 (Davison and Sell, 1972). DDT feeding induced naphthalene hydroxylation and P-450 in domestic pigeons (Grossman, 1978). Chlordene induced DMEs and P-450 in both pigeons and chicken (Kedo et al., 1977). PCBs induce haptic DME in chickens (Cecil et al., 1978). Among fish, the induction of drug-metabolizing enzymes has been observed as a result of exposure to environmental levels of petroleum, or by feeding high concentrations of PCBs, and by feeding or injecting polycyclic hydrocarbons (Table 7). Several carcinogens, both proven (benzidine, vinyl chloride, benzo(~)pyrene, etc.) and suspected (PCBs, DDT, lindane, cyclodienes) are widespread water pollutants. Refinery effluents induced hepatic AHH in brown trout and capelin (Payne et al., 1978: Payne, 1976) and cunner (Payne and May, 1979). Petroleum hydrocarbons, 3-MC, and 5,6-benzoflavone induced DME (but not P-450) (Stageman and Sabo, 1976), including aldrin epoxidase (Burns, 1976) in the Killifish (Fundulus heteroclitus). Injection of 3-MC. dibenzanthracene, TCDD induced P-450, AHH, and O-deethylase in several marine fish (James et al., 1977) and induction disappeared slowly with time (Philpot et al., 1976). Low levels of petroleum hydrocarbons (at 200 ppb in water) although inducing hepatic DME (Payne and May, 1979) lower hepatic lipogenesis in the Killifish (also in gill, muscle, and brain) and S t e n o t o m u s vesicolor (Stageman and Sabo, 1976). Fish liver microsomes can activate carcinogens and therefore can lead to hepatoma which is so common among fish (Ahokas, 1979). DDT can induce DME and its components in the mosquitofish (Chambers and Yarbrough, 1978; Wells et al., 1973) and rainbow trout (Buhler, 1966) (Table 7). Aroclor-1254 (1 ppm for 4 days) induced liver weight and protein concentration, aniline hydroxylase and AP N-demethylase in channel catfish (Hill et al., 1974). Varying diets have been implicated as a cause of induction of DME affecting chlordane toxicity to fish (Mayer et al,, 1978). TCDD induced AHH in flounder and little skate (James et al., 1977; Bend et al., 1979). Among invertebrates the induction has been observed more clearly in insects than in

Induction of drug-metabolizing enzymes

73

any other group. In houseflies DDT is a less potent inducer than dieldrin. In strains with high DME, epoxidase is induced by dieldrin (naphthalene hydroxylase and resistance to carbaryl also induced) to a greater extent than in those with low levels of DME, F1 hybrids between the two showed intermediate levels (Yu and Terriere, 1971). Cyclohexamide blocked the induced DME and protein synthesis but puromycin had no effect. DDT or dieldrin induce metabolism of DDT, aldrin, allethrin, propoxur, and diazinon (Table 8). DDT, cyclodienes, OPs, J.H. analogues induce P-450. Dieldrin induces P-450 (Matthews and Casida, 1970) along with DME in Orlando-DDT-resistant strains (Plapp and Casida, 1970; Yu and Terriere, 1971, 1972, 1973). DDT also induced P-450 in this strain (Tare et al., 1973) and a Diazinon-resistant strain (Perry et al., 1971). TOCP, TFP, DEP increased P-448 in a Diazinon-resistant but not in a Malathion-resistant strain (Perry et al., 1971). In the former strain, Malathion, tropital, MGK-264, and three substisubstituted phenyl-2-propropyl ether synergists shifted P-448 to P-450, with no effect on P-450 in the latter strain (Perry et al., 1971). In cockroaches, Periplaneta americana and Blattella germanica DDT and dieldrin treatment induced AHH activity in the fat body (Khan and Matsumura, 1972). DDT has been shown to induce DMEs in Triatoma infestans (Morello et al., 1971).

8.2. ORGANOPHOSPHATES(OPs)

Anticholinesterases are relatively poor inducers (Conney, 1967; Stevens et al., 1973) but repeated exposures to dosages below the LO5o may induce M F O and P-450 (Table 11). Interactions of OPs are biphasic in nature and either antagonism or synergism may result depending on the time interval between administration of the two agents. Thus, when administered as a single dose an OP can inhibit the metabolism of a particular drug during first several hrs (1-8 hr) after treatment and may stimulate the metabolism of the same drug 24 hr later or after chronic administration (Kato et al., 1964; Kamienski and Murphy, 1971). Such biphasic reactions (common with many combinations of insecticides and drugs) can result in extremely complex effects on biologic activity. The overall inhibitory action probably results from the combined effects of alternative substrate inhibition (Conney et al., 1967) and that resulting from the oxidative release and binding of reactive sulfur (Norman et al., 1974). However, their action on drug metabolism appears to be complex since different kinetic characteristics are observed with different compounds (Stevens et al., 1973). Thus inhibition of DMEs (in vitro metabolism of HB and ethyl morphine), prolongation of HB hypnosis by paraoxon (Rosenberg and Coon, 1958a, b; Stevens et al., 1973) in mice is due to a non-competitive activation of aniline hydroxylation. Repeated subacute administration for 3 to 10 days of parathion, paraoxon, disulfoton (and carbaryl) increases rate of HB and aniline metabolism in mice with a concommitant decrease in HB sleeping time (Stevens et al., 1973). However, doses required to produce these effects were equivalent to half LOso. Such repeated dosages induced P-450, ethylmorphine N-demethylase, N A D P H cytochrome-c-reductase, and N A D P H oxidase in rats and mice (Stevens et al., 1973). Rats fed 50 ppm of demeton showed severe effects during first four weeks of feeding and then they gradually recovered on continued feeding, and at 16th week showed no signs of poisoning even though the brain cholinesterase was 7 per cent of the untreated ones (Barnes and Denz, 1954). The death occurred when the initial treatment caused 80 per cent inhibition of diaphragm in 6 days but not if this occurred gradually in 20 days (McPhillips and Coon, 1966). Treatment with parathion (1.5 mg/kg/day in diet) made rats become only slightly more tolerant to parathion (see: Durham, 1967). Similarly, repeated small daily dosages of schradan made them slightly more tolerant to schradan (Rider et al., 1952). Repeated daily dosages of disulfoton (1.2 mg/kg, i.p.) produced typical cholinergic signs in 3 to 5 days; but after 8-12 days the animals became tolerant of continued dosing. The cholinergic receptors may become somewhat refractory to the stimulant action of acetycholine due to this treatment (Robinson et al., 1954; Krivoy and Wills,

74

M . A . Q . KHAN

1956). This induced tolerance does not appear to persist beyond the recovery of cholinesterase. Rats adopted to disulfoton showed cross-resistance to schradan but not to parathion (McPhillips and Coon 1966). Physostigmine and neostigimine extend PB hypnosis in rat (Kayaalp and Numanoglu, 1952). Parathion and TEPP had a similar effect in mice (Proctor et al., 1961, 1964; Proctor, 1964) which was blocked by various agents which favor adrenergic activity, including monoamine oxidase inhibitors and adrenergic amines, and atropine sulfate (central anticholinesterase effects) and not by atropine methylbromide (anticholinesterase with peripheral effects) (Proctor, 1965). Also schradan (with very little central effects) does not affect HB action. Thus these effects are not related with DME but could be related with the increase in cholinergic activity in central nervous system reversible by elevation of adrenergic activity (Proctor, 1965). Dogs surviving paraoxon became tolerant to further potentially lethal dosages of parathion (Barnes and Duff, 1954). Rabbits pretreated with DFP, however, became six times more sensitive to theophylline and theophylline ethylenediamine that produce corticol seizures (Johns et al., 1951). Men with day to day exposure to small amounts of parathion may attain blood cholinesterasc levels about 15 per cent of the normal without showing poisoning symptoms (Summerford et al., 1953). In spite of the well accepted biphasic response to OPs some workers have reported that chronic treatment of rats with several OPs can inhibit hydroxylation of drugs and steroids by liver microsomes (Rosenberg and Coon, 1958a; Welch et al.. 1959, 1967). The effects of induction of DME by drugs and insecticides on toxicity and metabolism of OPs depends on the balance between desulfuration (activation) and hydrolysis (detoxication) by DME. Treatment of rats with chlorpromazine (i.p,) increased the oral toxicity of parathion during first six hr (due to activation), but reduced it one day after the treatment (due to detoxication?) (Vurkovich et al., 1971). PB seemed to increase both activation and detoxication reactions in vitro (Neal, 1967, 1972: Alary and Brodeur, 1969) in rats; however, it stimulated the detoxication of parathion to a larger extent causing the urinary excretion of diethylphosphorothioic acid). Treatment of rats and mice with inducers (chlorcyclazine, cyclazine, PB, tolbutamide, SKF-525A, steroids) decreased toxicity of parathion, paraoxon, EPN, systox, disyston, delnav, phosdrin, trithion, and malathion (Murphy et al., 1959; Welch and Coon, 1964; McPhillips, 1965: Brodeur, 1967; O'Brien, 1967; DuBois et al., 1968; Menzer and Best, 1968: Alary and Brodeur. 1969: DuBois, 1971; Menzer, 1970) and similar effects may be seen with dietary DDT and dieldrin (Menzer. 1970; Menzer and Rose, 1971) (Table 10). Inducers increased acute toxicity of Schradan and Guthion, and OMPA (due to activation, potentiated by SKF-525A pretreatment) in rats (Murphy and DuBois, 1958) while reduced the toxicity of strychnine, zoxazolamine, meprobomate, and chlordane or lindane protected female rats against oral toxicity of parathion (Ball et al., 1954), aldrin protecting also against the intravenous dose of parathion as well as the oral dose of paraoxon and TEPP (Main, 1956). ~-HCH, chlorcyclazine, and tolbutamide reduced the toxicity of OMPA (and parathion but not of DFP) to rats (not seen with other inducers (Neubert and Schaefer, 1958; Takabataka et al., 1968). DDT and chlordane stimulated in vitro activation and detoxication of parathion in rats, while 3-MC pretreatment preferentially enhanced the activation (Chapman and Leibman, 1971). In mice, PB or chlorcyclazine decreases acute toxicity of malathion, parathion, EPN (Welch and Coon, 1964) and nikethamide decreased that of EPN (Table 11). 3-MC and chlordane respectively, reduced and stimulated both activation and detoxication of OPs while DDT stimulated only the hydrolysis (Chapman and Leibman, 1971). In mice, a 16 mg aldrin/kg dosage reduced the toxicity of paraoxon, malaoxon, Guthion, EPN, TEPP, DFP, and parathion (at even 1 mg aldrin/kg), but not of OMPA (Triolo and Coon, 1966a and b: Cohen and Murphy, 1972); protection against parathion being maximal 4 days after treatment. DDT, DDE (75 mg/kg) or chlordane protected against parathion but not against paraoxon; however, Chapman and Leibman (1971), Bass et al. (1972), and Black et al. (1973) saw no such protection.

Induction of drug-metabolizing enzymes

75

While inducers of DME lower the toxicity of OPs, the inhibitors (SKF-525A, CFT 1201) increase their toxicity; although reverse is true in the case of Guthion and Schradan (Murphy and DuBois, 1958). These inhibitors of DME enhance the protection by oximes in rats poisoned with OPs without degrading the oxime. Since the synergism is evident against anticholinesterases, a restraining action of the activation of OP would not explain it (Stern and Boskovic, 1960; Milosevic and Terzic, 1964). The potentiation of the toxicity of Co-Ral (by 4- to 6-fold) by PBO to rats is related with the inhibition of its detoxication (Robbins et al., 1959). However, protective action is not limited to phosphorothionates but extends to a variety of phosphates which are not detoxified by DME (Main, 1956; Welch and Coon, 1964; Triolo and Coon, 1966b; Alary and Brodeur, 1969; Menzer, 1970). TOCP and EPN potentiated the toxicity of malathion (Frawley et al., 1958; Murphy et al., 1959; DuBois, 1961)by blocking the metabolism of malathion or malaoxon (Murphy and DuBois, 1957; Murphy et al., 1959; Seume and O'Brien, 1960a). EPN inhibits only the carboxylester and not the phosphate ester attack (Seume and O'Brien, 1960b). Similar combinations of 30 out of 37 of the compounds showed similar inhibition of these ester bonds in rats (also in mice and in the American cockroach and housefly). Larger dosages of inducers can overload DME and thus cause potentiation of OPs (Durham, 1967), e.g. chlorpromazine can increase toxicity of mevinphos in rats, and promazine and diphenylthydantoin that of several OPs (Keplinger and Deichman, 1965). The duration and intensity of the action of OPs (Guthion, EPN, DBD) and drugs (HB) can be affected by hormonal differences between male and female rats older than one month of age. In females and young males prolonged administration of testosterone increased the metabolism by DME, of EPN and DBD, DMP, HB, morphine, methadone, mepridine, o-aminophenol (DuBois and Kinoshita, 1965; Murphy, and DuBois, 1958; Quinn et al., 1958). Reverse effects were seen in adult males, where prolonged administration of progesterone decreased hepatic metabolism of EPN, and DBD (Murphy and DuBois, 1958), but not of HB (Juchau and Fouts, 1966). Testosterone, methyltestosterone, estradiol, diethylstilbesterol, deoxycorticosterone, cortisone inhibited the toxicity of DMP (DuBois and Kinoshita, 1965). 8.3. OTHER INSECTICIDESAND SYNERGISTS Carbaryl did not potentiate the toxicity of OPs (Carpenter et al., 1961). Feeding pyrethrum (200mg/kg/day) to rats for 13 or 20 days showed induction of DME and P-450 (Springfield et al., 1973). Thanite does not potentiate toxicity of carbaryl in rats (Carpenter et al., 1961), but this and related cyanates synergize carbamates by inhibiting DME (E1-Sebah et al., 1964; Dorough and Casida, 1964). Methylene-dioxyphenyl compounds induce MFO and P-450 in mammals (Hodgson and Philpot, 1974). The effect is biphasic, a single dose initially inhibits DME for <24-36 hr and thereafter causes induction. PBO and tropitol inhibit during the 12 hr after treatment followed by induction in 24-48 hr (Kamienski and Murphy, 1971). The two processes may be completely separate and certain elements of inhibition may remain part of the stimulation. PBO induces DME and P-450 in rats (Conney et al., 1971; Wagstaff and Short, 1971) and mice (Matthews et al., 1970; Skrinjaric-Spoljar et al., 1971 ; Philpot and Hodgson, 1971a; Hodgson et al., 1974). Other inducers are Safrole (Parke 1970; Wagstaff and Short, 1971 ; Gray et al., 1972), isosafrole (Wagstaff and Short, 1971 ; Lake and Parke, 1971, 1972), and propylisome (Philpot and Hodgson, 1971b; Hodgson et al., 1974). "PBO prolonged barbiturate and zoxazolamine action (Fujii et al., 1968), slowed metabolism of BP (Falk et al., 1965), and increased acute toxicity of BP and griseofulvin (Catalano and Cullen, 1966) in rats. High doses of PBO inhibit metabolism of antipyrene, zoxazolamine and caused potentiation of PB and zoxazolamine in rats which was 100 times higher than seen in mice (Catz and Yafee, 1962; Catalano and Cullen, 1966). In newborn mice PBO increased acute toxicity and carcinogenecity of Freon (Campbell et al., 1964). In mice PBO and sesamex prolonged HB hypnosis (Fine

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and Molloy, 1964). SKF-525A enhanced the disruption of avoidance behavior by carbaryl and compound 10,854 (3-isopropylphenyl N-methyl carbamate) (Goldberg and Knack, 1964). In man PBO (0.7 mg/kg) induced metabolism of antipyrene (Catz and Yafee, 1962; Catalano and Cullen, 1966). In rats, safrole and isosafrole induce a modified P-450 (Parke, 1970; Lake and Parke, 1972) with increased binding of both type I and type II substrates (Ks for type II substrates is decreased but for type I is not affected). In mice, propylisome and PBO induce P-450 after 36 hr, and the ethylisocyanide pH equilibrium point and type I and type II binding ratios differ from controls only in the case of PBO (Philpot and Hodgson, 1971a; Hodgson et al., 1974). PBO can prevent the binding of carbon monoxide to P-450 in mice (and in houseflies) (Matthews et al., 1970: Philpot and Hodgson, 1971b).

9. EFFECTS OF INSECTICIDES AND OTHER XENOBIOTICS ON STEROID METABOLISM DME is more active in male than in female rats (after they are about 5 weeks old) due to differences in the balance of sex hormones. These differences affect the duration and intensity of the drugs (HB) and OPs (EPN, Guthion, DBD) (Conney, 1967). Such difference can be seen by the administration of chemicals that alter steroid metabolism or by direct administration of steroids. For example, in young males and females, prolonged administration of testosterone (and other steroidal hormones) increased DME activity towards EPN and DBD, increased the metabolism of EPN, DBD, D M P (lowered toxicity), HB, o-aminophenol, morphine, methadone, mepridine (DuBois and Kinoshita, 1965; Murphy and DuBois, 1958; Remmer, 1959). Reverse effects were seen in adult males where prolonged administration of progesterone decreased hepatic metabolism of EPN and DBD (Murphy and DuBois, 1958) but not of HB (Juchau and Fouts, 1966). Steroids are considered the normal body substrates of DME (Conney, 1967). Several structurally unrelated drugs and insecticides that stimulate DME also stimulate steroid hydroxylase and other in vivo effects of steroids. Treatment of rats for 4 days with diphenyl hydantoin, chlorcyclazine, norchlorcyclazine, orphenadrin, phenylbutazone, chlordane, DDT, o,p'-DDD induced estradiol metabolism by DME and decreased its concentration in and effects on uterus (Levin et al., 1968). 3-MC has little or no effect on hydroxylation of testosterone, 17-fl-estradiol, cortisol, cortisone, A4-androstene-3, 17-dione (Conney and Klutch, 1963; Conney and Schneidman, 1964). Chronic treatment with PB, phenylbutazone, or DDT stimulated hydroxylation of testosterone in the 16-~ to a greater extent than in the 6/3- or 7~- (Conney and Schneidman, 1964; Welch et al., 1967); while 3-MC stimulated 7~- and inhibited hydroxylation at 16~- (Kuntzman et al., 1968; Conney et al., 1973). Phenobarbital, chlordane, DDT induce progesterone hydroxylase, decrease concentration of progesterone and its metabolites in brain and body and decrease its anesthetic action (Conney, 1967). Phenobarbital enhances metabolism of androgens, estrogens, glucocorticoids and progestational steroids by DME and prevents the action of deoxycorticosterone, androsterone, A-androstene-3, 17-dione (Welch et al., 1971). PB and several drugs inhibited the action of estradiole, estrone, and diethylstilbestrol on the rat uterus by stimulating their metabolism by DME (Levin et al., 1968; 1969; Welch et al., 1967). Chronic treatment with PB inhibited the uterotrophic action of synthetic steroidal oral contraceptives in rats (Levin et al., i968). PB and chlordane treatment for several days inhibited growth-promoting effects on seminal vesicles of injected testosterone and testosterone propionate (Levin et al., 1969). OCs are potent stimulators of 17-/3-estradiol and esterone metabolism and decrease effects of estrogens on uterus (Welch et al., 1967; Kuntzman et al., 1964; Levin et al., 1968). Chronic treatment with pentobarbital inhibited the precocious ovulation of immature rats following estradiol treatment (Hagins et al., 1966). In immature females~ chlordane dieldrim heptachlor, toxaphene, Lindane,

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p,p'-DDD; p,p'-DDE treatment for several days inhibited the increase in uterine weight and esterone concentration in uterus on esterone administration (Conney and Burns, 1972). DDT, methoxychlor, o,p'-I)DT are estrogenic. In immature females, o,p'-DDT is uterotropic, bat, o,p'-DDD; m,p'-DDD; p,p'-DDD; or p,p'-DDE and p,p'-DDT had little or no estrogenic action (Conney, 1972). o,p'-DDT increased uterine weight in ovariectomized adults; 2 days after injection of o,p'-DDD absorption by uterus (in vivo) of the injected 17/3-estradiol was inhibited (Levin et al., 1968; Welch et al., 1969). o,p'-DDT (like 17/3-estradiol) induces (blocked by cyclohexamide and actinomycin) glycogen and RNA synthesis and augments several glycolytic and HMP shunt enzymes in the uterus of ovariectomized rat (Singhal et al., 1970). Glycogen in uterus as a response to esterogenic action of DDT and relatives (diphenylmethane, diphenylethane, triphenyl-methane) was active when p or p' position was unoccupied or occupied by an O H - or C H 3 0 - group. o,p'-DDT was the most potent inhibitor of the binding of estradiol-17/3 in the 8S uterine cytosol receptor in rats and mice (Kupfer and Bulger, 1976). o,p'-DDT and to a lesser extent other DDT derivatives have uterotropic activities (Conney et al., 1966; Conney and Burns, 1972) and increase uterine glycogen, o,p'-DDT is also estrogenic in mink (Duby et al., 1971). 20-200ppm DDT had no adverse effect on fertility and 1-15 ppm p,p'-DDT and o,p'-DDD had no effects on reproduction of rats (Ottoboni, 1969; Duby et al., 1971; Wren et al., 1970). One mg of o,p'-DDT injected into 2-, 3-, or 4-day old baby rats advanced puberty, induced persistent estrus and caused the development of follicular cysts in ovaries and a reduction in number of corpora lutea (Heinrichs et al., 1971). DDT can act like exogenous estrogens and androgens (Heinrichs et al., 1971; Ottoboni, 1969), and PCBs, polychlorinated triphenyl, phenothalol, phenophtalene are also estrogenic. Kepone decreased fertility in female rats and mice (Ambrose et al., 1953), it caused constant estrus in mice (Huber, 1965), while aldrin disturbed estrus cycle in rats (Ball et al., 1954). In mice 7 ppm had no effect on fertility with the exception of the C-57 strain of black mice in which 200-300ppm DDT decreased reproductive success (Bernard and Gaertner, 1969). DDT does not induce the microsomal hydroxylation of estradiol in mice as it does in rats (Conney, 1967). When PB, BNF, antipyrene, spirorolactone and refampicin were administered to guinea pigs to study the irreversible binding of ethynyloestradiol to liver microsome, refampicin produced the greatest (220 per cent) increases in the irreversible binding, while PB produced the greatest increase (172 per cent) in P-450 and NADPH-cytochrome-creductase (210 per cent) (Park et al., 1978). Estrogenic activity of DDT derivatives is thus well documented (Kupfer and Bulger 1976). Methoxychlor is demethylated to HPTE (2,2-bis (parahydroxy)-l,l,l-trichloroethane by hepatic DME in rats. HPTE inhibited the binding of estradiol-17B to estrogenic receptors in uterine cytosol (Nelson et al., 1976; Bulger et al., 1978) and increased estradiol-17/3 uptake by rat uteri in vitro (Welch et al., 1969). Methoxychlor and other DDT derivatives increased uterine glycogen (Bitman and Cecil, 1970) and ornithine decarboxylase activity (Bulger et al., 1978). Phenobarbital, diphenylhydantoin, and phenylbutazone stimulate DME in guinea-pigs that hydroxylate cortisol in 6/3-position (Kuntzman et al., 1966; Werk et al., 1964), and in rats o,p'-DDD can stimulate in vitro metabolism of cortisol to polar metabolites (Kupfer and Peets, 1966). This stimulation by o,p'-DDD may be due to accelerated metabolism of cortisol to highly polar 17-hydroxymetabolites that are poorly extractable into chloroform, but not due to a decrease in urinary 17-hydroxycortocoids by its action on adrenals. Daily treatment of humans with 6 to 9 g of o,p'-DDD stimulated urinary excretion of 6/%hydroxycortisol and decreased the chloroform-extractable 17-hydroxycorticoids in urine. It caused remission of clinical and biochemical features of Cushing's syndrome before affecting the cortisol excretion (Southern et al., 1966; 1969). In humans, metabolism of cortisol to 6/3-hydroxycortisol is also induced by PB, N-phenylbarbital, diphenylhydantoin, phenylbutazone, antipyrene, DDT; o,p'-DDD (Kuntzman et al., 1966,

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1968; Conney, 1972); and N-phenylbarbital alters the excretion of testosterone metabolites (Southern et al., 1969). Inhibitors of DME and steroid metabolism augment the action of steroids in animals. e.g. SKF-252A augments the action of esterone on rat uterus (Axelrod et al., 1954), it also inhibits the induction of hepatic tyrosine transaminase by cortisol (Kupfer and Peets, 1967). Carbon tetrachloride inhibits uterotropic action of o,p'-DDT, so the latter may not be converted to the estrogenic metabolite(?) (Welch et al., 19691. It inhibits the metabolism of esterone and 17/~-estradiol (Levin, 1970) and hence, the utertropic action of the latter. Carbon tetrachloride (0.06 to 0.67 ml/kg) inhibits the action of drugs (after 3 hr), decreases P-450 and these effects persist for 24 hr and return to normal after 7 days. OPs also inhibit steroid hydroxylations (Welch et al., 1967; Rosenberg and Coon, 1958a). Among birds, the eggshell thinning problems so related with OCs has been hypothesized to be mediated through alteration in metabolism of steroids by induced DME (Risebrough et al., 1968; Gillett, 1968). In chicken and quail, o,p'-DDT is reported to be estrogenic (Cecil et al., 1972; Bitman and Cecil, 1970; Bitman et al., 1968). In pigeons DDT induced metabolism of 17/Lestradiol, progesterone, and testosterone (Peakall, 1967), while PCBs induced 17/~-estradiol metabolism in both pigeons and American kestrel (Risebrough et al., 1968; Lincer and Peakall, 1970). DDT (1 ppm) induced in l~i~'o metabolism of estrogen and there was less 17/~-estradiol in blood, less deposition of calcium and delayed egg laying (Peakall, 1970). In quail kepone had marked estrogenic effect (McFarland and Lacy, 1969). DDT affects eggshell thickness and calcium deposition in Japanese Quail (Bitman et al., 1969) and Alaskan Peregrine Falcon (Cade et al., 1971). The deposition of medullary bone (source of calcium for eggshell) is largely controlled by 17/3-estradiol (Simkiss, 1967) and (a) enhanced metabolism of estrogen, or (b) the occupation of estrogenic binding sites by DDT metabolites, might impair eggshell formation. In insects, juvenile hormone (J.H.) analogues and ecdysterone can induce DME and P-450 (in houseflies) (Yu and Terriere, 1971). In insects, hormones regulate molting and metamorphosis, etc., and large changes in DME are seen at different stages of life cycle and at different ages (Arias and Terriere, 1962; Khan, 1969, 1970; Price and Kuhr, 1971; Perry and Buckner, 1970; Yu and Terriere, 1971). DME is greatest in actively feeding last instar larvae and declines during less active stages. In houseflies a sudden increase in DME before pupation may be related with high ecdysone titers (Yu and Terriere, 1971). In adult flies fl-ecdysterone stimulates DME. The relationship between DME activity and levels of hormones (J.H. and ecdysone) during development does hold with many insects (Bowers, 1976; Horn, 1971 ; Robbins et al., 1971), although an inverse relationship occurs in the silk worm (Samia cynthia racini) (Shaaya and Karlson, 1965). Interactions between hormones and DME could also result in increased metabolism of hormones, but this has not been investigated. Ecdysterone stimulates DME in larvae (Yu and Terriere, 1971). Cecropia J.H. and hydroprene (ethyl-3,7,11-treithyldodeca-2,4-dienoate) stimulated DME and P-450 in Isolan-resistant strain of houseflies (Terriere and Yu, 1973). 10. EFFECTS OF INDUCERS ON OTHER ENZYMES DME are responsible for the metabolism and synthesis of several endogenous molecules such as steroid hormones, fat-soluble vitamins, fatty acids, bilirubin, cytochromes, pyridine nucleotides, etc. Induction of DME may alter the metabolism and action of these and other biomolecules. Barbiturates accelerate metabolism and conjugation of bilirubin by DME and stimulate bile flow (Catz and Yafee, 1962; Roberts and Plaa, 1967). PB can increase bilirubin concentration in serum of patients with chronic hepatic cholestasis as well as in jaundiced (congenital, non-hemolytic) infants (Yaffe et al., 1966; Thompson and Williams, 1967; Crigler and Gold, 1969). Treatment of pregnant mothers for 2 weeks before childbirth with 60 mg PB can prevent hyperbilirubinemia for first few

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days in the newborn (Maurer et al., 1968; Trolle, 1968) by decreasing half-life of bilirubin in plasma (Crigler and Gold, 1966). Treatment of patients with nonhemolytic jaundice with DDT can also lower bilirubin concentration in serum for several months (Thompson et al., 1969). In rats, DDT can increase hepatic glucuronyltransferase. Prolonged treatment with anticonvulsants can cause increased metabolism of vitamin D (Dent et al., 1970; Hahn et al., 1972) and deficiency in vitamin K (Mountain et al., 1970), the former causes osteomalacia, reduction in calcium and increase in alkaline phosphatase in serum. PB can also cause hypercalcium, renal calcinosis, and loss of weight (Richens and Rowe, 1970) in rats, while spironolactone and DDT lower vitamin A in serum (Tuchweber et al., 1970; Seward et al., 1970). Prolonged feeding of sodium phenobarbitone in diet (0.1 per cent w/w) for 4-24 weeks to rats showed a marked increase in liver size along with the induction of microsomal protein, P-450, DME, and UDPG-transferase. Urinary excretion of D-glucaric and L-glucaric acid from D-glucuronic acid and L-ascorbic acid and xyletol was increased (Lake et al., 1978). It has significant effect on vitamin D3 metabolism and plasma folate level (Rising, 1979). Cessation of feeding showed the return of DME to control levels faster than the urinary excretion (Lake et al., 1978). In man, in addition to increasing D-glucaric acid excretion, phenobarbitone lowered serum folate levels (Latham et al., 1973). Di-demethylated metabolite of methoxychlor, HPTE, simulated uterine ornithine decarboxylase in rats (Bulger et al., 1978). Methoxychlor and other DDT derivatives increased uterine glycogen in rat (Bitman and Cecil, 1970), o,p'-DDT increased estradio1-17/3 uptake by rat uterus in vitro (Welch et al., 1969). A number of chemicals including DDT, Mirex, TCDD, PCB (Aroclor-1254), and BNF induce one or the other, or both of the 05 or 7 aldehyde dehydrogenase isozymes in rat liver cytosol. After TCDD administration (one i.p. injection of 75 #g/kg) ALDH isozyme activity is about 100-fold greater than the normal liver ALDH activity for a long time with a broad peak at 10 to 14 days remaining high for another 10 days, In certain strains of rats PB increases by 10- to 30-fold the activity of the 05 ALDH isozyme (Lindahl et al., 1978). DDT and Mirex induced the q~ isozyme. 3-MC and PCBs induce both 7 and 05 isozymes. Carcinogens 2-acetylaminofluorene and dimethylaminoazobenzene induce several cytosolic ALDH isozymes (oc~-isozymes) unique to hepatoma in several strains of rats (Deitrich et al., 1978; Lindahl et al., 1978). Induction of P-450 is followed by profound changes in liver cells. Repeated dosages increase activities of several microsomal enzymes such as esterases, reductases, conjugases (Remmer and Merker, 1963). Increase is much higher in microsomes from SER, being up to 2-fold in the overall protein and lipid content. Non-MFO enzymes, e.g. G-6-phosphatase, ATP-ase, 5-nucleotidase are not induced. Several cytoplasmic enzymes, such as UDP-glucose dehydrogenase (Touster and Hollmann, 1961), some transaminases and conjugases (Schellhas et al., 1965; Remmer, 1963), and several others (Remmer and Merker, 1963; Kuntzman et al., 1966) are also induced, as well as a few mitochondrial enzymes and oxygen consumption of mitochondria is increased (Orrenius and Ernster, 1967). Other increases are: (i) incorporation of 14C-acetate and 17C-mevalonate into cholesterol (ii) 7-c~-hydroxylation of cholesterol (iii) deiodination of thyroxin, (iv) demethylation of methylated purines, 6-dimethylaminopurine and 6-methylaminopurine (Conney, 1967; Kuntzman, 1969). 3-MC and TCDD are potent inducers of rat liver DTdiaphorase, the latter being about 17,000 times more effective than the former (Beatty and Neal, 1976). Other enzymes induced by TCDD in laboratory mammals are deltaALA synthetase, UDP-glucuronyl transferase, glutathione transferase B, glutamateoxaloacetate transaminase, lactic dehydrogenase, alkaline phosphatase (Beatty et al, 1978). TCDD is about 100,000 times more effective in elevating UDP-glucuronyl transferase in rat liver and this may involve both an increased synthesis and/or decreased degradation of this protein (Beatty et al, 1978). In the rat hepatic supernatant, the activity of aldehyde dehydrogenase that is dependent on NAD is increased up to 10-fold after PB administration for 3 days. The effect is

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genetically controlled and is inherited as an autosomal dominant characteristic. The mechanism is apparently unrelated to other drug-induced increases in enzyme activity such as those that occur in the hepatic DMEs (Deitrich, 1971). Cytosolic glutathione-Stransferases are inducible by PB or PAH in rodent liver (Baars et al., 1978; Hales and Neims, 1977; Mukhtar and Bresnick 1976a, 1976b; Poland and Kende, 1976; Kaplowitz et al., 1975), mouse lung (Mukhtar and Bresnick 1976a); and rat kidney (Clifton and Kaplowitz, 1977; Clifton et al., 1975). In rat liver different types of GSH-S-transferases may be induced by 3-MC, PB, and TCDD as judged by qualitative differences in their inductive effects (Baars et al, 1978). PCBs can stimulate Na+-K + ATP-ase activity in brain and kidney of rats (Narbonne et al., 1978). Aldrin and chlorcyclazine modify liver plasma A-esterase titers (Main, 1956; Ghazal et al., 1964; Triolo and Coon, 1966b; Welch and Coon, 1964; Triolo et al., 1970; Cohen and Murphy, 1972); there is an increase in liver and serum B-aliesterase activity (Crevier et al., 1954) by single oral dose of aldrin, dieldrin, chlordane, DDT (Ball et al., 1954). Increases in serum aliesterase have been observed in mice by aldrin (Triolo and Coon, 1966a; Cohen and Murphy, 1972) and chlorcyclazine (Welch and Coon, 1964) as well as in liver aliesterase by aldrin (Cohen and Murphy, 1972). Increased aliesterase should bind and subsequently reduce oxygen analogues of OPs (their anti-cholinesterase activity). Ethionine blocks aldrin-induced increases in serum B-esterase and liver-A-esterase and can provide protection against orally administered paraoxon (Triolo and Coon, 1966b). There is good correlation between paraoxon toxicity to rats and the free plasma levels on DDT, dieldrin, and chlordane treatment in rats (Triolo et al., 1970) and on aldrin treatment in mice (Triolo and Coon, 1969; Triolo et al., 1970). Four days post treatments at which the maximum protection by aldrin against paraoxon coincided with that at which maximum stimulation of plasma aliesterase was observed, and since paraoxon completely inhibited this enzyme at 10 6 M, aliesterase could be the major paraoxon-binding protein in plasma (Triolo et al., 1970; Cohen and Murphy, 1972). Possible importance of other binding sites should not be discounted, however, and it is of interest that an increase in serum to slarginine methyl ester hydrolysis is seen following treatment of mice with chlorcyclazine (Welch and Coon, 1964). Low concentration of paraoxon were detoxified by a non-enzymatic binding to non-critical sites in rat liver plasma (Lauwerys and Murphy, 1969). 125 mg TOCP/kg of rat which itself caused no inhibition of brain ChE but which completely blocked those binding sites (in vitro) caused a rapid increase in inhibition of brain ChE and a 2-fold increase in paraoxon toxicity (Cohen and Murphy, 1972). Foreign compounds differ in both the degree and the duration of storage in body tissues. At any particular continuous dosage level, the easily excreted ones (water soluble drugs, most OPs, carbamates, pyrethroids, rotenoids, juvenoids, etc.) reach relatively low concentration in any tissue (most drugs are completely excreted in man in a few days to a few weeks), while poorly excreted ones (OCs) reach relatively high concentrations, especially in tissues for which they have a special affinity (e.g. bone-seekers are stored for longest periods in bones, OCs stored in adipose tissue for considerably long periods). If a tolerated dosage is repeated at intervals for a sufficient period, the resulting storage may increase rapidly at first and then more and more gradually until it reaches a steady state. If dosage is stopped before a steady state is reached, total body storage will decrease, but the storage in tissues (which equilibrate only slowly with the circulating blood) with a high affinity for the compound may remain unchanged or even increase for a time. This pattern of storage is due to the tendency for the rate of loss at a particular time to be directly related to the concentration stored at that instance. The relatively low rate of blood flow to adipose tissue, and bones is important in determining the distribution of compounds to these tissues following a single dose. The rate of blood flow may not be important in determining the level at which a steady state of storage is achieved in connection with repeated dosage. Inducers of DME have, at least theoretically, the capacity to markedly alter biotransformation and storage of xenobiotics in adipose tissues. When two or more xenobiotics

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are administered simultaneously or when one chemical is administered while a previous chemical is still stored in the body, interactions between the two can alter their action and metabolism. This may involve mechanisms such as interference with g.i. absorption, displacement from protein binding or lipid storage, and interference with the metabolism and excretion. Such interactions can be affected by the type of the chemical (DDT or cylcodienes), dosage (low or high), species (dog or rat), sex (male or female rat), etc. A xenobiotic that is primarily detoxified by DME can either become more toxic by the presence or administration of the other if the interaction inhibits the detoxication, or less toxic if detoxication is enhanced. Inhibition of metabolism may result in the accumulation of toxic concentrations of the xenobiotic in various tissues. Whereas induction may rapidly decrease its concentration in plasma to sub-toxic levels. For example, in patients, chloramphenicol or bishydroxycoumarin which inhibit the metabolism of tolbutamide by DME may result in a hyperglycemic effect (Kristensen and Jansen, 1967; Kuntzman et al., 1966), while PB and other inducers causing increased metabolism may decrease the anticoagulant action of coumarin (Sellers et al., 1972). Such interactions are very important in drug therapy. However, since OCs are stored in body for rather long periods of time the effects of inducers and inhibitors of DME on their storage, metabolism as well as of these OCs on the action and metabolism of other insecticides and xenobiotics has received considerable attention. Since the level of storage achieved at equilibrium in connection with any given rate of dosage is conditioned by the DME activity induced by that dosage, and since compounds differ in their ability to induce DMEs, there is a relationship between the form of the curve relating dosage to equilibrium storage and that relating time to storage after dosing is stopped. In the simplest case the equilibrium storage is directly related to dosage and the semilog plot of storage loss is a straight line. For OCs the slope of the curve relating storage to dosage is less and the semilog plot of storage is curved--both reflecting that excretion is more efficient at higher storage levels. This prolonged curvature (when dosage is terminated after storage equilibrium) is distinguishable from the initial curvature often seen in the first few hours or days of excretion following a single dose. Unlike prolonged curvature based in a gradual slowing of metabolism, initial curvature may represent merely rapid clearing from blood followed by slower clearing from other compartments. Compounds influencing the rates of accumulation, metabolism, or excretion of OCs cause changes in their steady-state storage in tissues. The rate of storage loss of some OCs, in some mammals, resembles that of drugs (Robinson et al., 1969), and is dependent on the concentration for which equilibrium is sought. The loss in the case of DDT is fastest for DDD, intermediate for DDT and slowest for DDE. OCs stimulate DMEs and their own metabolism which thereby decreases their own storage gradually resulting in less induction of DME. If the dosage is large the excretion rate will be large. DDT induces biotransformation of dieldrin and greatly reduces its storage in many tissues (Street and Sharma, 1976). In rats, DDT at 50 ppm in food reduced the storage of dieldrin and heptachlor (fed at 1 ppm before DDT feeding) by over 90 per cent of the control. DDT was active when administered prior to or simultaneously with dieldrin. By extrapolation it was suggested that some effect on dieldrin could be expected to occur at 0.5-1 ppm of DDT (Street, 1968). Feeding DDT reduced dieldrin (fed at 1 ppm) storage by 3-fold and 15-fold at 5 ppm (about 1.26 mg/kg/day), and 50 ppm DDT, respectively; if dieldrin was fed at 10 ppm then its depletion by DDT was about half that at 1 ppm. The storage of DDT, which depends on DDT dosage was not affected (Street, 1968; SIreet and Blau, 1966). The effect persisted for more than 6 weeks after cessation of DDT feeding (Street et al., 1966b). Several DDT metabolites and analogs caused a similar although less marked induction of dieldrin storage in rats (DDT > DDE > DDD > DDMU) (Street, 1968). Similar effects of DDT have been reported also in mice (Keplinger and Deichman, 1965), pigs and sheep (Street et al., 1966b). However, dieldrin retention in beagle dogs fed for 10 months on diets containing either 0.6 mg aldrin/kg or a combination of 0.3 mg aldrin + 12 mg DDT/kg/day remained unchanged and 9 weeks J.Pn.

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after feeding aldrin (0.3 mg/kg/day) following the feeding of 12 mg D D T / k g / d a y for 10 months increased the storage of DDT + DDD + DDE by 2-fold in female and by 4- to 6-fold in males. No effect on dieldrin storage was observed in either hens or trout fed DDT + dieldrin (Street, 1968). Dieldrin depletion in rats has been shown to be affected by barbiturates (at 1200 to 1800ppm in diet), phenobarbital, barbital, heptabarbital, seconal, etc. as well as by s-chlordane, methoxychlor and DDE (Cueto and Hayes, 1965; Street et al., 1966b; Street. 1968; Engebreston and Davison, 1971); whereas AP, phenylbutazone, tolbutamide, and chlorpromazine as well as 3-MC (500 ppm) have been less effective (Street, 1968; Straw et al., 1965; Street and Blau, 1966). Phenobarbital also depicts storage of HCH in rats (Koransky et al., 1964). Although the depletion of dieldrin is associated with the increase in hydrophilic metabolites of dieldrin in feces and urine, the latter being enhanced 17-fold by DDE in rats (Street and Chadwick, 1967; Street 1968), suggests the involvement of the induction of DME, yet the inhibitors of protein synthesis (Actinomycin D, ethionine) do not block this process (Street, 1968). Also, DDT and barbiturates are almost equally effective as DME inducers yet the former is about 40-times more reactive in reducing dieldrin storage (Street et al., 1966b; Street, 1968). DDT, especially at high dosages, may displace dieldrin (especially at low levels) from the proteins making it available for metabolism by induced DME followed by excretion (Moss and Hathway, 1964; Street, 1968; Matsumura and Wang, 1968; Menzer and Rose, 1971; Eliason and Posner, 1971). Therefore, both DME induction and displacement from protein storage may be responsible for dieldrin storage. Depletion of dieldrin is also seen in dairy cattle, cows, by continuous treatment with PB (Reeder, 1969; Cook and Wilson, 197l; Davison, 1977). In humans, continuous diphenylhydantoin therapy markedly reduces DDT residues (Street and Sharma, 1976). Other combinations of pesticides (aldrin, aremine, carbaryl, carbophenothion, chlordane, DDT, delnav, diazinon, dieldrin, endrin, methoxychlor, parathion, toxaphene, several nematocides) were synergistic towards each other while the combinations of CNS depressant drugs with OCs decreased the toxicity of the latter (Keplinger and Deichman, 1965). Two year feeding of rats on diets containing 8 common flavoring agents with 6 commonly used pesticides and synergists (aldrin, DDT, malathion, 2, 4-D, pyrethrin, PBO) had no effects on toxicity (Taylor et al., 1965).

11. INDUCTION OF DME IN EXTRA-HEPATIC TISSUES Liver is the main organ for the metabolism of foreign chemicals. However, other organs and tissues may be active to some degree in biotransformation of xenobiotics. For example, rat diaphragm, kidney, and brain metabolize DDT in vitro (Judah, 1969), slices of rabbit skin rapidly degrade OPs (about 20 per cent of paraoxon is hydrolyzed in 1 hr per grm) (Fredrickson et al., 1961); rabbit lung similarly metabolized parathion to paraoxon as well as hydrolyzed it (Neal, 1972); small intestine of rat hydrolyzes carbaryl and conjugates naphthol (Pekas and Paulson, 1970). In extra-hepatic tissues, the low levels of DME activity and absence of ultrasensitive analytical assays (Lake et al., 1973; Fouts, 1970, 1970a) make it hard to accurately quantify the inductive or inhibitory effects of foreign chemicals. The activity of AHH in lung and intestine is largely dependent on exogenous inducers (Wattenberg, 1970, 1971). Only the small intestine of rats fed the regular diet plus turnip greens, broccoli, cabbage or brussel sprouts had marked AHH activity (Wattenberg, 1971). Intestine appears to be especially responsive to polycyclic hydrocarbons (Dao and Yogo, 1964; Gelboin and Blackburn, 1964a; Gentil and Sims, 1971) resulting in P-448 (Zampaglione and Mannering, 1973); phenothiazine derivatives induce AHH (Wattenberg and Leong, 1965); tri-ocresyl phosphate stimulates parathion conversion to paraoxon by 4-fold (Lynch and

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Coon, 1966). In mice oral treatment with PB induces o-demethylation of 7-ethoxycoumarin several-fold in small intestine (Lehrman et al., 1973; Scharff and Ullrich, 1973), as well as ethylmorphine N-demethylation (Thomas et al., 1972). In rats, phenothiazine stimulates AHH in liver, kidney, lung, spleen, thymus and intestine, PCBs (Aroclor-1254) stimulates AHH in liver, lung, kidney, intestine, and placenta (Alvares, 1977). PB exerted slight inductive effects on kidney DME but had no effect on lung DME (Gram et al., 1977). Carbon tetrachlordine inhibited the hepatic and pulmonary DME, but had no effect on kidney DME, it increased UDP-glucuronyl transferase in liver and kidney (Gram et al., 1977). Although phenothiazine and polycyclic hydrocarbons do not induce AHH in adrenals, these chemicals effectively protect against dimethylbenzanthracene-induced adrenal necrosis (Dao and Varela, 1966; Wattenberg and Leong, 1965). Only metapyrone appears to be stimulating adrenal AHH. BP and 3-MC both induce some P-450 in kidneys; in rats P-450K and AHH are induced with BP (Grundin et al., 1973), 3-MC (Gelboin and Blackburn, 1964a, 1964b; Nebert et al., 1972; Warren and Bellward, 1978), or phenothiazine (Uehleka and Greim, 1968) and this may not increase P-450K. 3-MC also induced aminoazo dye N-demethylase (Gilman and Conney, 1963). The P-450K from only (and not controls) BP-treated rats give type I spectra on addition of BP which was specific to BP-hydroxylation. However, the induction is species-specific, e.g. PB increases DME, b5 and P-450K in rabbits (Uehleka, 1968; Uehleka and Greim, 1968) but not in rats (Gilman and Conney, 1963, Jakobson et al., 1970). The response of lung AHH is species-specific, in rats phenothiazine, 2-phenylthiazine, 3-MC, chlorpromazine, //-napthoflavone, Ag-tetrahydrocannabinol, or cigarette smoke induced AHH (Gelboin and Blackburn, 1964a, 1964b; Wattenberg and Leong, 1965, 1966; Wattenberg et al., 1962; Welch et al., 1971; Witschi and Saint-Francois, 1972; Warren and Bellward, 1978). Rabbit lung is less responsive to polycyclics than rats, and PB does not induce AHH (Gram et al., 1977) but did slightly increase aminopyrene N-demethylation, aniline hydroxylation and parathion oxidation (Neal, 1972; Poore and Neal, 1972). Other tissues sensitive to inducers are: skin to PAH (Alavares et al., 1973a, 1973b), thyroid and testes to 3-MC (Wattenberg and Leong, 1962), placenta to BP (Welch et al., 1969) and PCBs (Alvares, 1977), and mammary gland to dimethylbenzanthracene (Tamulski et al., 1973). 12. CONCLUSIONS Differences in DMEs or in their ability to be induced may explain some of the differences in susceptibility to poisoning associated with interactions of compounds, and with interspecies and intraspecies (age, sex, etc.) differences. The ability of a chemical to affect the metabolism of another drug or chemical in humans and other animals deserves serious consideration. [Humans used to alcohol (alcoholics), exposed to OCs (occupationally), and carcinogens (cigarette smokers) have induced DME (Beckett and Triggs, 1967; Kato et al., 1969; Kolmodin-Hedman et al., 1969)]. In humans the induction or inhibition of DME by drugs, alcohol, cigarette smoke, other environmental chemicals in food, water and air acting independently or collectively should be taken seriously in chemotherapy for disease, physiological disorders or for carcinogenicity. Also, the effect of foreign chemicals on the metabolism of lipids, steroids, vitamins, etc., may have an important bearing on physiology and behavior of humans and other animals. Of great concern is the presence of metabolite (of afflotoxins, polycyclic aromatics, halogenated benzenes, cyclodienes) and environmental products (such as photoisomers of cyclodienes) and yet undetectable hazardous contaminants (such as TCDD, nitrosamines) in environment and living organisms. Since DME can be induced by hormones and other body constituents (Conney, 1967), and by food (Wattenberg, 1971), the phenomenon of induction is not limited to toxic chemicals alone.

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ABBREVIATIONS The a b b r e v i a t i o n s used AP= An= AHH = AIA = ALAS = ATP = BA= BNF = BP= BPA = CO= Co-Ral = CNS = DDA = DDD = DDE = DDT = DFP = DMP = 2,4-D = DNA = EM= epox. = EPN = eth, = FDA = G-6-P = JHHB= HCH = LD50 = 3-MC = Me-MAB = ND, N-Dem. = NT= OCs = OD= OMPA = OP= PAH = PNA, p N A = PB= PBB PBO PCB = P-450 = RNA = SKF-525A = TCDD = TEPP = TOCP = UDPG = = =

are as follows: aminopyrene aniline aryl h y d r o c a r b o n h y d r o x y l a s e allyl i s o p r o p y l a c e t a m i d e delta-aminolevulonic acid s y n t h e t a s e adenosine triphosphate benzanthracene

beta-naphthoflavone benzo(:0pyrene benzphetamine carbon monoxide O,O-diethyl-O[3-chloro-4-methyl-2-oxo-2H-l-benzopyran-7-Yl ] phosphorothioate central n e r v o u s system 1,l-bis(p-chlorophenyl) acetic acid 1,1 -bis(p-chlorophenyl) e t h a n e 2,2-bis(p-chlorophenyl)- 1,1-dichloroethylene

1, l -b is(p-chlor o phen yl)- l , l, l -trich lor oeth ane diisopropyl fluorophosphate dimethyl phthalate 2 , 4 - d i c h l o r o p h e n o x y a c e t i c acid d e o x y r i b o n u c l e i c acid ethyl m o r p h i n e epoxidation ethyl. 4 - n i t r o p h e n y l p h e n y l p h o s p h o n o t h i o n a t e isocyn. = ethyl i s o c y a n i d e Food and Drug Administration glucose-6-phosphate juvenile hormone hexobarbital hexachlorocyclohexane m e d i a n lethal dose 3-methylcholanthrene 3-methyl m o n o m e t h y l a m i n o a z o b e n z e n e N-demethylation neotetrazolium organochlorines O-demethylation octamethylphosphoramide organophosphate polycyclic a r o m a t i c h y d r o c a r b o n s

para-nitro-anisole phenobarbital polybrominated biphenyl piperonyl butoxide polychlorinated biphenyl c y t o c h r o m e P-450 r i b o n u c l e i c acids diethylaminoethyl diphenyl propylacetate hydrochloride 2,3,7-8-tetrachlorodirenzo-p-dioxin tetraethyl p y r o p h o s p h a t e triorthocresyl phosphate u r i d i n e d i p h o s p h o g l u c u r o n i c acid

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