Pharmacogenetics of drug metabolism

TIPS - October I980

4,; >uhhtrstcs and Inhihltor\.

Pharmacogeneticsof drug metabolism

affinit!

cholrnc or cocamc) order

Thi\ dlffcrcncc of

is for many \uhsrra;e\ of

bifunctional

(like acct! I

nor prearcr than one

magnltudc: m&cute\

however.

for

dccJmcthtmium

the or

succinylcholine. the drfference IS exceptionally large. about t\*o orders of map-

W. Kalow

nitude. The maximal reaction rates (V,,,) :‘w gcncrally not veq different for the two enzyme variants regardless of sub\tratc

~kpe. The clinical Importance of the Genetic variation in drug metabolizing capacity deserves attention nor oni! in terms o,f occurrence of attpical cstrrase is almost inter-individual but also in terms ofinter-ethnic differences. cntlrel! confined to the serious modlfica-

Sourcesof variation of drug-metabolizing enyThere

are

amount olizing There

or

three

ways

composition

enzyme

in which of

drugmetab-

systems are

can be inducible

controlled.

enzymes.

are enzymes depending on imprinting, there are constitutional

two of these three control

Enzyme

there and

enzymes. At least systems affect

one or other of the important P45Ckontaining ases (MFOs).

the

cytochrome

mixed-function

oxygen-

induction must be looked at as

structural or regulator) genes. C’onstitutivc enzymes in this sense are. for example.

the isoniazid-metabolizing acetyltransferax and the plasma cholinesterasc.. the cytochromc-dependent ently

are

constitutive

Some of

MFOI

appar-

enzymes

as for

instance those located in mitochondria.

It is

Besides these fundamental regulatoq mechanisms on amount or structure of an

genetic typing. gene frcqoenrles habe bc:cn determined in almost 3~W!~t) C‘aucastan

enzyme. secondary factors can modify the

subjects and manv thousands from other populations. Soni of the tarioub racial groups have a high an inctdence ofat>p~ai

activity of any given set of eqmes.

For

anism against chemical adversity. In years

some cases. co-factor supply or competitive

time-limited

of study. NeberP

phenomenon

and his colleagues have

investigated in inbred strains of mice the particular MFO system which is inducible by such carcinogens as methylcholanthrene or TCDD (dioxin). It turned out that the main

difference

non-inducible

between

inducible

and

strains was the nature of a

Since the enqmc i> in pla\rna. the occurrence of variants can hc tested tn vitro: they show a simple mcndclian pattern of inheritance. Becaust of the acces\ibility of human plasma cholmestera\e to

which plays a major role as a defence mech-

adaptive,

prolongation of ~uccm~lcholine actlon hut often a qualitative difterence apparent as ‘dual block’.

likely, though hard to prove. that there arc such constitutive MFOs in the microwmes.

membrane-bound enzymes. this could be the lipid composition of the membrane. in

an

tlon of action of the muscle relaxant succin>lcholine. Thus modification is ntbtonI> a

phenomena could modify enzyme activit!.

Somesalient observations in man In this context. onl) certain aspects of the topic can be highlighted. Chdinestemse. One of the most straightforward and therefore instructive sets o!

shown in Table I. Another variant. the silent gene. Hhich produces an rnz!me type that IS virtually devoid crf rnz)mc occurs actlvit). among Alaskan

much

more

frequentI>

Eskimosthan in an> other

group. Isl~~rfa:id-n~r~ti~no/irin~ uc~rt~ltrim.sJk.W The enzyme IKSU \ in li\cr and the gcncrir ditfercnccs do not ,:ppar ro mvohe 5truc-

cytosolic receptor protein. the occupation of which by the inducer would initiate the

data concerns plasma cholinesteraw’.

induction

human lymphocytes has shown. this same

variant is the so-called atypical cholin:sterase. obviously representing an amino acid

tural variants bur dlflqsrences in the amount (of enzyme. Assessment in t+ro of the

system operates in man. Thus, in these

exchange, The atypical variant has a loHer

cases, the genetic influence is exerted upon

affinity

acetylator sratus requires the adminisrrcltlon of a test drug which IS usualI! tsoniazid

process. As work

on isolated

pharmacologically

important

than the usual enzyme

.L\

esterase as do Caucasians. A comparison bctHeen Caucasians and Orientals ib

structural

for most

a control protein rather than upon the drug metabolizing enzyme itself. Imprint@ by a drug has been dcmonstrated recently in rats’. Diphenylhydantoin given monoamine

to a pregnant rat affected oxidase activity in the male

offspring. It is probably wise to assume that imprinting is not confined to diphenylhydantoin and to rats, but that it is adult

a widely occurring biological phenomenon.

If susceptibility to imprinting by a particular drug or chemical were genetically variable, the prenatal nature-nurture interaction would be hard to recognize ?tndeven harder to sort out in adults. Finally, there are constitutive enzymes. that is, enzymes that are not subject to major, selective modification by environmentat factors but which may show interindividual variation due to alilelism in

’ Values calculated from obsenrd frrquenc? v,i hztrn~npl~tti ‘Japanese. ’ British. ‘Chinese. ‘Data of Playferrtal.’ re-%valysed.

or sulfadimidine (sulphamethazinc). The acetylation capacity teprcscnis a menC’nrrrasmwIs d&an trait, whereby slow acetybrors are Onen~rir -_ homo~go~s, that is. they have a double Mean Numben Mean Numbers dose of the gene c~asirtg stow ac~~tylation. 1 SF tested r SF teswd Most test systems do not a!tow a distinction between homozygous (‘rapid-rapid’) and 3’-Hydroxyewobarhiul~ hcterozygous (‘slow-rapid’) rapid acetyl(amr~barbitdimelalwlite. ation capacity of individuals. although phtln mkrmingmine) CHydroxydehriroquinra there is a considerable statistical difference (~hrisnquinc mctah4itc, between the two gcnotypcs as groups’. % d dose in urine during g h) This has an often neglected conscAntipyrim clearance’” quence. In population studies involving (units bascdon mcasurcmcnts approximatt+ 2000 Caucasians and 2000 of cmtcentraticmin saliva) the percentage of Slow Japanese, aeetyiators among the Caucasians was a Data by V. Ottbn. W-k ‘Iltcsi~. ‘Twnntc~. 19X0. The puhlished method tjf data evnluatbn’ has nclt been used since there appeared to be indepndent variation of debriwquine axcrelinn. found to be 58.6% and among the Japan“The mean values are estlmat~~ fmm 1.F. Fig. 1. the SE frum text ~n~~~ti~~n. esc 12.0% (Tabie I). These figures are properly comparable because the stow was found to he abundant in the Swiss coumarol. diphenylhydantoin. halothane. acetylators are homozygotes in both population and therefore referred lo as nortriptylinc. phenylbutazone. sparteine. populations; however. Caucasian fast ‘normal’ has its optimal activity at pH 11. and tolbutamide. All of these drugs are acetylators and Japanese fast ao:;ttylators while the optimum for thr ‘ntypical’ variant metabolized at least partially by the MFO cannot be direciiy compared because the is at pH 8. At physiologicail pH, ethanol is systemE. The length of this list and the variformer are mostly heterozygotes while the rnet~~l~edi~ v&o about five times more ety of drugs involved makes it likely that latter consist of almost equal numbers of rapidly by ‘atypical’ than by ‘normal’ under similar experimental conditions. homozygotes and hetcrozygotcs. If rapid ADH. The ‘atypicai ADH’ in Europe is substantial heritability would bc found for metaboii&s capatity is a contributing present in about 10% of the population but the mcraboiizting capacity for most other cause to isoniazid-induced liver di mage. it in approximately 90% in the Japanese drugs. could be that the Japanese po;>ulation. The type elf genetic control has not been population (Table 1). This finding might hon gozygous suggest that most Japanese would tend to investigated f
may not rcvcal the prcscncc of a sper !fic biotransformation defect. It is not always possible, on the basis of experimental

or clinical

obscrvalions.

tcr

distinguish between multigenic anJ mono-

assign the OUWI

of the diffcrencc\

to gcncric or cnrmmmcntal This

lightI!

facton.

IS the stage ;It which UC arc.

in

respect tooxidation by MFO\(Tahlc II). It is very likely that some part of the r&u-

gcnic inheritance. but if thiscln be done it ib

lated differcnccs

a useful distinction because the tcvo types

dehrisoquine)

of inheritance allow different

terms of gene frequency uhilc other parts

dictions and provide

types of pre-

a different

basis for

research. If one wants to account for the occurrence

of

population,

the proper

a monogenic

trait

measure

in

(e.g. tho\c for h>drr,x!-

can soon hc cxprc\wd

may turn out to be determined

In

or mtlu-

enced by nutritional factor<.

a

is gene

Reading lit

frequency (or the frequency of a particular genotype in Table I). If one can count gene frequencie:

in ethnic groups. there is no

doubt that differrnccs

rncountend

have a

genetic basis. In all other cases. inter-ethnic variation

can only be expressed as differ-

ence in average values; then it is wise not to

Methylxanthines: possible mechanisms of action in brain Daniel P. Cardinali Methylxanthine-containing

beverages

Caffeine is the major active principle in all

were used in many ancient cultures as CNS stimulants. Coffee, the most popular of

three beverages, while throphylline and theobromine are present in smaller

these beverages. madr its initial appearance in Yemen near thz middle of the fif-

amounts. In spite of their unique pharmacological properttes. there is a sur-

teenth century and since that time has enjoyed almost universal assimilation into

prising lack of information about Ihe mechanism of action of meth! Isanthincs m

cultures

the brain. compared with other. mt)re modem, psychotropic drugs. Instead. and

world.

and

societies

throughout

the

In spite of being the most widely

used psychotropic drugs less is know about the methylxanthine

mechanism

of action

owing to the presencr of methqlxanthilrs in the diet of numerous hz,nan com-

than any other psychotropic agents. This article summarizes the current view of how

munities.

methylxanthines

mutagenic and teratogrnic effects.

act on the brain (Fig. 1).

Methylxanthines

belong to a chemical

have

considerable

been

This

devoted

article

summarizes

the

analysis of the publisheli data leabe% this reviewer. and hopefull) trill also Icake the

are three

important

and

uric acid.

natural

methylxan-

thines - caffeine, theophylline and theobromine - all of them able to stimulate the CNS.

In

addition.

methylxanthines

used as cardiac stimulants,

arc

methylxanthines

on

thz

of

current

adenosine,

standpoint. there

mechanism

efforts possihlc

v&s

hypoxanthine

the

their

group of purine bases which includes such as guanine. important compounds From a pharmacological

on

research to

action

C‘NS.

01

Critical

reader. with the feeling that much more information is needed Wore a drfimtc answer

t ) the question as to ho\r and u here

methylxanthines

act on hrnin is obtamcd.

diuretic agents

and bronchodilators. Methylxanthines hold the distinction of

being the most widely utilized psychotropic drugs. They are most often consumed in the form of coffee, tea and mate, the national drink in Argentina, Uruguay. Paraguay and southern regions of Brazil.

Methylxanthmes as CNS stimulants Methylxanthines

can stimulate all parts

of the CNS provided high enough Lxmcentrations aie attained; caffeine is more powerful

than theophylline.

and rheobro-

mint has the lowest activity in this rcspcct.