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Kwashiorkor
Medical Hypotheses
14: 401-406,
1984
KWASHIORKOR Gladys M. Reid, O.B.E.
25 Gilchrist
Street, Te Aroha, New Zealand.
ABSTRACT Kwashiorkor kills millions of young children in the tropical Third The World (1). It was believed to be a disease of protein starvation. medical team headed by Professor Ralph Henrickse of the Liverpool School of Tropical Medicine (1) has discovered that aflatoxin, a fungus toxin, may be the triggering factor in this disease which also impairs liver function (1). In New Zealand, we have a pasture fungus, the spores of which produce a liver toxin that has killed millions of animals this century and impaired the performance of millions more (2). New Zealand is a pastoral farming country with 70 million sheep and several million cattle. We now protect the animal with zinc medication. This paper describes the similarities between Kwashiorkor and the mycotoxic liver disease in New Zealand livestock, known locally as It describes briefly my discovery (2) that pharmacoFacial Eczema. logical doses of zinc protected farm animals from pasture contaminated with the spores of the fungus Pithomyces chartarum, which contains the This paper proposes that Kwashiorkor and Facial toxin sporidesmin. Eczema are diseases with similar beginnings and a common end.
INTRODUCTION Reid (2) outlines a brief history of the mycotoxin-induced liver disease Warm, humid, autumn weather promotes the of New Zealand livestock. growth of fungus Pithomyces chartarum on dead pasture litter and plant The spores of the fungus produce the hepatotoxin sporidesmin. debris. Study of this animal liver disease has been a major project in New Zealand for half a century. The approach today is direct animal pre-treatment with zinc. Salts of this metal have been shown (2,3) to provide excellent protection against the harmful effects of the mycotoxin.
401
Munday (4) discovered that sporidesmip toxicity involved superoxide generation by autoxidation and we were dealing with tissue injury and self destruction by free-radicals catalysed by a toxic di-sulphide Antioxidants (which Zinc inhibits this process. cyclic autoxidation. act as free-radical scavengers) have been shown to give protection against sporidesmin (5); their protective activity was additive with that of zinc. Zinc is known to protect animals from a variety of other toxic compounds, as shown in the extensive studies of Chvapil (6.7,8,9) He also found (6) that zinc protected macro-molecules, biomembranes, sulfhydryls and other thiols in biological molecules, from oxidation Another important factor in protecting against tissue and destruction. injury is glutathione, which destroys free-radicals and peroxides (16). I propose to show that glutathione, zinc, selenium antioxidants, and animal protein all play a liver protective role against noxious agents. I propose to show that impaired liver function and protein catabolism provide the environment for liver disease to flourish. A diseased liver cannot tolerate a high protein diet either. Resistance to liver poisons such as sporidesmin and aflatoxins depends on factors that inhibit the promotion of increased production and excretion of toxic metabolic products. When toxic metabolites enhance tissue damage, increased metabolism during the detoxification process promotes tissue injury. The metabolic process is then itself toxic. This paradox is of great significance. Newell (2) states that aflatoxin blood levels are ten times higher in Kwashiorkor children but by contrast these patients have lower levels in urine. A parallel to this paradox occurs in Logan, et al. (1982) (ll), where relatively inactive indoles are converted to toxic metabolites by the mixed function oxidase system in acute bovine pulmonary emphysema. Chvapil (7) sums up the problem of increased toxicity of breakdown products being more reactive than the initial foreign compound.
DISCUSSION Zinc Pre-Treatment
in Protecting Against Tissue Injury
Chvapil (7) states that the Mixed Function Oxidase (MFO) system in the liver is an activation system, not always a detoxifying system. He points out that the liver MFO system is involved in activation of some chemical carcinogens. He points out that zinc protects against many hepatotoxins produced by the MFO system. Zinc reduces the activity of the MFO system and is, therefore, involved in reducing the formation of lipid peroxides (7,9). Chvapil quotes evidence (7) to substantiate the proposal that zinc ions block Aflatoxin B1 (AFB1) metabolism and protects polyunsaturated fatty acids from peroxidation. Similarly, zinc protects against pyrrolizidine alkaloids (18) whose toxicity is again attributable to the formation of active metabolites by the MFO system. Other investigators have found similar problems with the MFO system. Dietert, et al, (lo), investigating embryonic toxicity of AFBl, 402
comment on the precocious MFO activity of the embryonic human liver. Logan, et al. (11) comment on a similar problem with ruminants exposed to the intestinal toxin 3-Methyl-Indole (3MI). The animals with the more efficient MFO systems were placed at a distinct disadvantage in survival terms when exposed to 3MI. The metabolic products of 3MI were considered the ultimate toxins, just as the matabolites of Aflatoxin are the ultimate toxins. Munday (4) showed that sporidesmin can undergo a cyclic reduction/ autoxidation reaction in the presence of thiols. During the autoxidation reaction, the superoxide radical is formed: SDM(SH), Sporidesmin dithiol
+
20,
----+
SDMS,
+
2 o,-
Sporidesmin di-sulphide
In vitro, zinc prevents superoxide formation by reacting with sporidesmi to prevent autoxidation. In all these cases, therefore, zinc serves to prevent the formation oE harmful metabolic products. Glutathione (GSH) Glutathione is capable of reacting with harmful free-radicals. In association with the selenium-containing enzyme, glutathione peroxidase, it destroys peroxides (16). Mitchell, et al. (15) discuss GSH and drug-induced tissue lesions. They state that many foreign compounds are metabolised by the liver. They state, like Chvapil, that these studies demonstrate how chemically stable compounds, after activation to toxic substances, can produce serious tissue lesions including neoplasia, hepatic and renal necrosis, bone marrow aplasia and other injuries. They state these studies also indicate a role for sulfhydryl-containing compounds, particularly glutathione, in protecting tissues from such toxic reactions. After the liver is depleted of GSH a toxic metabolite then combines with liver molecules essential to the life of hepatocytes. Depletion of cellular GSH has been shown to increase the toxicity of many compounds while cysteine, a GSH precursor, is protective. Modification of toxicity in this manner has been demonstrated for many compounds including acetaminophen (19), bromobenzene (ZO), carbon tetrachloride (21), 3-methylindole (12), pyrrolizidine alkaloids (22), and, significantly, aflatoxin (23).
CONCLUSIONS The clue to aflatoxin toxicity in Kwashiorkor appears to be the tenfold higher level of aflatoxin in blood and lower levels in urine, suggesting covalent binding of noxious agents to vital cells in the absence of protective factors. This finding suggests an MFO enhanced activity producing toxic metabolites and free radicals. Two avenues toward preventing the disease can
403
therefore be envisaged: (1) Inhibition of the production of the harmful metabolites; and (2) Destruction of the metabolites befQre they can destroy vital cell components. It would appear that human liver protection could be greatly enhanced by dietary means. Dietary animal protein - the major source of sulphur aminoacids and therefore GSH - would help to maintain cellular glutathione levels. Fortification of animal protein foods with antioxidants is indicated wherever free radicals are generated by toxic food (17). Selenium fortification may also give useful protection. It must be borne in mind that GSH peroxidase loses activity when exposed to hydrogen peroxide in the absence of donor substrate (GSH) (16). Protection of GSH is crucial. Liver necrosis was prevented when depleted hepatic GSH was less than 80%. Zinc,to inhibit the generation of toxic metabolites, could play a key role in Kwashiorkor prevention. Serum levels of this metal are dramati tally decreased in children suffering from the disease (24). Chvapil links serum albumin as one of the major carriers of zinc (8). He states it has been suggested that albumin depletion, due either to liver impairment or increased protein catabolism, and in chronic disease, results in increased urinary excretion and a subnormal zinc nutritional state. The importance of the liver in preserving the nutritional balance is reflected not only in albumin-zinc storage but in the balance of essential fatty acids, he says. This could be the heart of the Kwashiorkor protein depletion in the face of, and superimposed upon, an animal protein deficiency in the diet lacking in protective cysteine. Aflatoxins and sporidesmin are two mycotoxins that kill by destroying protective factors and by promoting destructive factors. Medication for Kwashiorkor protection needs to use this knowledge. The suggestion that pro-oxidants and free radicals are involved in Kwashiorkor is endorsed by the fact that oxidant-killing of the malaria parasite is documented (13) and Kawashiorkor patients are said to be less susceptible to malaria (1). Uncontaminated food for man and animal is worth striving for, but in the meantime from the New Zealand experience, there are dietary factors to protect against some liver toxins, against glutathione depletion, free radicals, and pro-oxidants. The dietary needs of children exposed to contaminating liver poisons in their food are far removed from the dietary needs of children nurtured under ideal conditions. This was the livestock problem we faced in New Zealand when the grazing animal ate toxic pastures and I found that protecting the animal with zinc was the most practical approach (2). Protective measures for children could easily be tackled on a wider 404
base, by fortifying animal protein such as milk powder. Relief organisations involved in Kwashiorkor and famine relief should undertake a crash programme in liver protection from fungus toxins, from the evidence already available from the New Zealand experience and from the evidence incriminating aflatoxins (I). We became very familiar with emaciated, pot-bellied, runty calves with faded coats dying of starvation in the midst of plenty. Fibrosis of the liver or fatty liver, oedema, lethargy, and scouring were all the aftermath of sporidesmin toxicity and liver failure.
ACKNOWLEDGEMENTS I thank Dr. Rex Munday for valuable assistance and Coral Reid for typing the script.
REFERENCES 1.
Newell
2.
Reid G.M. The Pharmacological Role of Zinc: Evidence from Clinical Studies in Animals. Medical Hypotheses, 7: 207-15, 1981.
3.
Towers N.R. and Smith B.L. Facial Eczema Prevention. Revised recommendations for zinc dosing 1983. Ministry of Agriculture and Fisheries Media Services, F.P.P. 77, p 496.
4.
J. Treating for Starvation may kill. 18 August 1983, 471.
New Scientist,
Munday R. Studies on the mechanism of toxicity of the mycotoxin .sporidesmin. 1. Generation of superoxides radical by sporidesmin. Chem. Biol. Interactions, 41 (1982), 361-74. Elsevier Scientific Publishers Ireland Ltd.
5.
Munday R, Manns E, and Mortimer P.H. Effect of Antioxidants on the Toxicity of the Facial Eczema Toxin Sporidesmin in Sheep. Proceedings of the New Zealand Society Animal Production, 1983.
6.
Chvapil M. New Aspects in the Biological Role of Zinc: A stabiliser of macromolecules and biological membranes. Life Sci., 13: 1041-49, 1973.
7.
Ludwig J.C. and Chvapil M. Mechanisms of action of metal ions of hepatocytes. From Inflammatory Diseases and Copper, Edited by John R. Sorenson. The Humana Press, U.S.A., 1982, 565-80.
8.
Chvapil M. and Koopman C.F. Age and other factors regulating wound healing. Otolaryngologic Clinics of North America, Vol. 15, No. 2, May 1982, 259-70.
9.
Chvapil M, Kern J, Misiorowski R, and Weinstein P.R. Endogenous Antioxidants and Rate of Maondialdehyde Formation. Central and Peripheral Nervous Systems, Experimental Neurology, 78, 765-74, 1982.
10.
Dietert R.R., Bloom S.E., Quresche M.A and Nanna U.C. Hematological Toxicology following Embryonic Exposure to Aflatoxin Bi. Proceedings Sot. Exp. Biol. Med., 173, 481-85, 1983.
405
11.
Logan A, Selman I.E., Wiseman A, Allan E.M. and Pirie H.M. Experimental Production of Diffuse Pulmonary Fibrosis and Alveolitis in Cattle: the effect of repeated dosage with 3, Methylindole. Res. Vet. Sci., 36, 97-108. 1982.
12.
Norerini M.R., Carlson J.R. and Breeze R.G. Effect of Glutathione Status on Covalent Binding and Pneumotoxicity of 3Methylindole, in Goats. Life Sci., 32, 449-58. Pergamon Press, 1983.
13.
Cox, F.E.G. Oxidant Killing of the Malarial Parasite. Nature, 302, p 19, 3 March 1983.
14.
Hoffman A.J. and Discher C. Chlorpromazine Sensitized Photodynamic Oxidation of Sulfhydryl Groups in Biological Molecules. Arch. Biochem. Biophys., 126, 728-30, 1968.
15.
Mitchell J.R., Hinson J.A. and Nelson S.D. Glutathione and Druginduced Tissue Lesions. In Glutathione Metabolism and Function, Ch. 25, p 357. Eds. Irwin M. Aries and William B. Jacoby. Raven Press, New York, 1976.
16.
Flohe Leopold, Gunzler Wolfgang Amandus and Ladenstein Rudolf. Glutathione Peroxidase. In Glutathione: Metabolism and Function, Ch. 8, 126. Eds. Irwin M. Aries and William B. Jacoby. Raven Press, New York. 1976.
17.
Reid, Gladys M. Scurvy: Old Disease - New Insight. Medical Hypotheses, 11, 167-69, 1983.
18.
Miranda, Cristobel L; Henderson, Marilyn C; Reed, Ralph L; Schmitz, John A; Buhler, Donald R. Protective action of zinc against Pyrrolizidine alkaloid-induced hepatotoxicity in rats. Journal of Toxicology and Environmental Health, 2, 359-366, 1982.
19.
Prescott L.F. and Critchley J.A.J.H. The Treatment of Acetaminophen Poisoning. Ann. Rev. Pharmacol. Toxicol., 3, 87-101, 1983.
20.
Jollow D.J., Mitchell J.R., Zampaglione N., and Gillette J.R. Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence of 3,4_bromobenzene oxide as the hepatotoxic metabolite. Pharmacology, 11, 151-69, 2974.
21.
Rechnagel Richard 0. and Glende Eric A.G. Carbon Tetrachloride Hepatotoxicity: An example of lethal cleavage. C.R.C. Critical Reviews in Toxicology, 281, 1973.
22.
Hayashi Y. and L,alichJ.J. Protective Effect of Mercaptoethylamine and Cysteine against Monocrotaline Intoxication in Rats. Toxicol. and Applied Pharmacol., 11, 36-43, 1968.
23.
Hatch Roger C., Clark J. Derrell, Anant V. Jain, Mahaffey Edward A. Experimentally-induced Acute Aflatoxicosis in Goats treated with Ethyl Maleate, Glutathione Precursors, or Thiosulphate. Am. J. Vet. Res., 5, 505-11, 1979.
24.
Burger F.J. Changes in Trace-Element Concentration in the Sera and Hair of Kwashiorkor Patients. In Trace Element Metaboiism in Animals (2), 671-74. Eds. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz. University Park Press, Baltimore, 1974.
406
14: 401-406,
1984
KWASHIORKOR Gladys M. Reid, O.B.E.
25 Gilchrist
Street, Te Aroha, New Zealand.
ABSTRACT Kwashiorkor kills millions of young children in the tropical Third The World (1). It was believed to be a disease of protein starvation. medical team headed by Professor Ralph Henrickse of the Liverpool School of Tropical Medicine (1) has discovered that aflatoxin, a fungus toxin, may be the triggering factor in this disease which also impairs liver function (1). In New Zealand, we have a pasture fungus, the spores of which produce a liver toxin that has killed millions of animals this century and impaired the performance of millions more (2). New Zealand is a pastoral farming country with 70 million sheep and several million cattle. We now protect the animal with zinc medication. This paper describes the similarities between Kwashiorkor and the mycotoxic liver disease in New Zealand livestock, known locally as It describes briefly my discovery (2) that pharmacoFacial Eczema. logical doses of zinc protected farm animals from pasture contaminated with the spores of the fungus Pithomyces chartarum, which contains the This paper proposes that Kwashiorkor and Facial toxin sporidesmin. Eczema are diseases with similar beginnings and a common end.
INTRODUCTION Reid (2) outlines a brief history of the mycotoxin-induced liver disease Warm, humid, autumn weather promotes the of New Zealand livestock. growth of fungus Pithomyces chartarum on dead pasture litter and plant The spores of the fungus produce the hepatotoxin sporidesmin. debris. Study of this animal liver disease has been a major project in New Zealand for half a century. The approach today is direct animal pre-treatment with zinc. Salts of this metal have been shown (2,3) to provide excellent protection against the harmful effects of the mycotoxin.
401
Munday (4) discovered that sporidesmip toxicity involved superoxide generation by autoxidation and we were dealing with tissue injury and self destruction by free-radicals catalysed by a toxic di-sulphide Antioxidants (which Zinc inhibits this process. cyclic autoxidation. act as free-radical scavengers) have been shown to give protection against sporidesmin (5); their protective activity was additive with that of zinc. Zinc is known to protect animals from a variety of other toxic compounds, as shown in the extensive studies of Chvapil (6.7,8,9) He also found (6) that zinc protected macro-molecules, biomembranes, sulfhydryls and other thiols in biological molecules, from oxidation Another important factor in protecting against tissue and destruction. injury is glutathione, which destroys free-radicals and peroxides (16). I propose to show that glutathione, zinc, selenium antioxidants, and animal protein all play a liver protective role against noxious agents. I propose to show that impaired liver function and protein catabolism provide the environment for liver disease to flourish. A diseased liver cannot tolerate a high protein diet either. Resistance to liver poisons such as sporidesmin and aflatoxins depends on factors that inhibit the promotion of increased production and excretion of toxic metabolic products. When toxic metabolites enhance tissue damage, increased metabolism during the detoxification process promotes tissue injury. The metabolic process is then itself toxic. This paradox is of great significance. Newell (2) states that aflatoxin blood levels are ten times higher in Kwashiorkor children but by contrast these patients have lower levels in urine. A parallel to this paradox occurs in Logan, et al. (1982) (ll), where relatively inactive indoles are converted to toxic metabolites by the mixed function oxidase system in acute bovine pulmonary emphysema. Chvapil (7) sums up the problem of increased toxicity of breakdown products being more reactive than the initial foreign compound.
DISCUSSION Zinc Pre-Treatment
in Protecting Against Tissue Injury
Chvapil (7) states that the Mixed Function Oxidase (MFO) system in the liver is an activation system, not always a detoxifying system. He points out that the liver MFO system is involved in activation of some chemical carcinogens. He points out that zinc protects against many hepatotoxins produced by the MFO system. Zinc reduces the activity of the MFO system and is, therefore, involved in reducing the formation of lipid peroxides (7,9). Chvapil quotes evidence (7) to substantiate the proposal that zinc ions block Aflatoxin B1 (AFB1) metabolism and protects polyunsaturated fatty acids from peroxidation. Similarly, zinc protects against pyrrolizidine alkaloids (18) whose toxicity is again attributable to the formation of active metabolites by the MFO system. Other investigators have found similar problems with the MFO system. Dietert, et al, (lo), investigating embryonic toxicity of AFBl, 402
comment on the precocious MFO activity of the embryonic human liver. Logan, et al. (11) comment on a similar problem with ruminants exposed to the intestinal toxin 3-Methyl-Indole (3MI). The animals with the more efficient MFO systems were placed at a distinct disadvantage in survival terms when exposed to 3MI. The metabolic products of 3MI were considered the ultimate toxins, just as the matabolites of Aflatoxin are the ultimate toxins. Munday (4) showed that sporidesmin can undergo a cyclic reduction/ autoxidation reaction in the presence of thiols. During the autoxidation reaction, the superoxide radical is formed: SDM(SH), Sporidesmin dithiol
+
20,
----+
SDMS,
+
2 o,-
Sporidesmin di-sulphide
In vitro, zinc prevents superoxide formation by reacting with sporidesmi to prevent autoxidation. In all these cases, therefore, zinc serves to prevent the formation oE harmful metabolic products. Glutathione (GSH) Glutathione is capable of reacting with harmful free-radicals. In association with the selenium-containing enzyme, glutathione peroxidase, it destroys peroxides (16). Mitchell, et al. (15) discuss GSH and drug-induced tissue lesions. They state that many foreign compounds are metabolised by the liver. They state, like Chvapil, that these studies demonstrate how chemically stable compounds, after activation to toxic substances, can produce serious tissue lesions including neoplasia, hepatic and renal necrosis, bone marrow aplasia and other injuries. They state these studies also indicate a role for sulfhydryl-containing compounds, particularly glutathione, in protecting tissues from such toxic reactions. After the liver is depleted of GSH a toxic metabolite then combines with liver molecules essential to the life of hepatocytes. Depletion of cellular GSH has been shown to increase the toxicity of many compounds while cysteine, a GSH precursor, is protective. Modification of toxicity in this manner has been demonstrated for many compounds including acetaminophen (19), bromobenzene (ZO), carbon tetrachloride (21), 3-methylindole (12), pyrrolizidine alkaloids (22), and, significantly, aflatoxin (23).
CONCLUSIONS The clue to aflatoxin toxicity in Kwashiorkor appears to be the tenfold higher level of aflatoxin in blood and lower levels in urine, suggesting covalent binding of noxious agents to vital cells in the absence of protective factors. This finding suggests an MFO enhanced activity producing toxic metabolites and free radicals. Two avenues toward preventing the disease can
403
therefore be envisaged: (1) Inhibition of the production of the harmful metabolites; and (2) Destruction of the metabolites befQre they can destroy vital cell components. It would appear that human liver protection could be greatly enhanced by dietary means. Dietary animal protein - the major source of sulphur aminoacids and therefore GSH - would help to maintain cellular glutathione levels. Fortification of animal protein foods with antioxidants is indicated wherever free radicals are generated by toxic food (17). Selenium fortification may also give useful protection. It must be borne in mind that GSH peroxidase loses activity when exposed to hydrogen peroxide in the absence of donor substrate (GSH) (16). Protection of GSH is crucial. Liver necrosis was prevented when depleted hepatic GSH was less than 80%. Zinc,to inhibit the generation of toxic metabolites, could play a key role in Kwashiorkor prevention. Serum levels of this metal are dramati tally decreased in children suffering from the disease (24). Chvapil links serum albumin as one of the major carriers of zinc (8). He states it has been suggested that albumin depletion, due either to liver impairment or increased protein catabolism, and in chronic disease, results in increased urinary excretion and a subnormal zinc nutritional state. The importance of the liver in preserving the nutritional balance is reflected not only in albumin-zinc storage but in the balance of essential fatty acids, he says. This could be the heart of the Kwashiorkor protein depletion in the face of, and superimposed upon, an animal protein deficiency in the diet lacking in protective cysteine. Aflatoxins and sporidesmin are two mycotoxins that kill by destroying protective factors and by promoting destructive factors. Medication for Kwashiorkor protection needs to use this knowledge. The suggestion that pro-oxidants and free radicals are involved in Kwashiorkor is endorsed by the fact that oxidant-killing of the malaria parasite is documented (13) and Kawashiorkor patients are said to be less susceptible to malaria (1). Uncontaminated food for man and animal is worth striving for, but in the meantime from the New Zealand experience, there are dietary factors to protect against some liver toxins, against glutathione depletion, free radicals, and pro-oxidants. The dietary needs of children exposed to contaminating liver poisons in their food are far removed from the dietary needs of children nurtured under ideal conditions. This was the livestock problem we faced in New Zealand when the grazing animal ate toxic pastures and I found that protecting the animal with zinc was the most practical approach (2). Protective measures for children could easily be tackled on a wider 404
base, by fortifying animal protein such as milk powder. Relief organisations involved in Kwashiorkor and famine relief should undertake a crash programme in liver protection from fungus toxins, from the evidence already available from the New Zealand experience and from the evidence incriminating aflatoxins (I). We became very familiar with emaciated, pot-bellied, runty calves with faded coats dying of starvation in the midst of plenty. Fibrosis of the liver or fatty liver, oedema, lethargy, and scouring were all the aftermath of sporidesmin toxicity and liver failure.
ACKNOWLEDGEMENTS I thank Dr. Rex Munday for valuable assistance and Coral Reid for typing the script.
REFERENCES 1.
Newell
2.
Reid G.M. The Pharmacological Role of Zinc: Evidence from Clinical Studies in Animals. Medical Hypotheses, 7: 207-15, 1981.
3.
Towers N.R. and Smith B.L. Facial Eczema Prevention. Revised recommendations for zinc dosing 1983. Ministry of Agriculture and Fisheries Media Services, F.P.P. 77, p 496.
4.
J. Treating for Starvation may kill. 18 August 1983, 471.
New Scientist,
Munday R. Studies on the mechanism of toxicity of the mycotoxin .sporidesmin. 1. Generation of superoxides radical by sporidesmin. Chem. Biol. Interactions, 41 (1982), 361-74. Elsevier Scientific Publishers Ireland Ltd.
5.
Munday R, Manns E, and Mortimer P.H. Effect of Antioxidants on the Toxicity of the Facial Eczema Toxin Sporidesmin in Sheep. Proceedings of the New Zealand Society Animal Production, 1983.
6.
Chvapil M. New Aspects in the Biological Role of Zinc: A stabiliser of macromolecules and biological membranes. Life Sci., 13: 1041-49, 1973.
7.
Ludwig J.C. and Chvapil M. Mechanisms of action of metal ions of hepatocytes. From Inflammatory Diseases and Copper, Edited by John R. Sorenson. The Humana Press, U.S.A., 1982, 565-80.
8.
Chvapil M. and Koopman C.F. Age and other factors regulating wound healing. Otolaryngologic Clinics of North America, Vol. 15, No. 2, May 1982, 259-70.
9.
Chvapil M, Kern J, Misiorowski R, and Weinstein P.R. Endogenous Antioxidants and Rate of Maondialdehyde Formation. Central and Peripheral Nervous Systems, Experimental Neurology, 78, 765-74, 1982.
10.
Dietert R.R., Bloom S.E., Quresche M.A and Nanna U.C. Hematological Toxicology following Embryonic Exposure to Aflatoxin Bi. Proceedings Sot. Exp. Biol. Med., 173, 481-85, 1983.
405
11.
Logan A, Selman I.E., Wiseman A, Allan E.M. and Pirie H.M. Experimental Production of Diffuse Pulmonary Fibrosis and Alveolitis in Cattle: the effect of repeated dosage with 3, Methylindole. Res. Vet. Sci., 36, 97-108. 1982.
12.
Norerini M.R., Carlson J.R. and Breeze R.G. Effect of Glutathione Status on Covalent Binding and Pneumotoxicity of 3Methylindole, in Goats. Life Sci., 32, 449-58. Pergamon Press, 1983.
13.
Cox, F.E.G. Oxidant Killing of the Malarial Parasite. Nature, 302, p 19, 3 March 1983.
14.
Hoffman A.J. and Discher C. Chlorpromazine Sensitized Photodynamic Oxidation of Sulfhydryl Groups in Biological Molecules. Arch. Biochem. Biophys., 126, 728-30, 1968.
15.
Mitchell J.R., Hinson J.A. and Nelson S.D. Glutathione and Druginduced Tissue Lesions. In Glutathione Metabolism and Function, Ch. 25, p 357. Eds. Irwin M. Aries and William B. Jacoby. Raven Press, New York, 1976.
16.
Flohe Leopold, Gunzler Wolfgang Amandus and Ladenstein Rudolf. Glutathione Peroxidase. In Glutathione: Metabolism and Function, Ch. 8, 126. Eds. Irwin M. Aries and William B. Jacoby. Raven Press, New York. 1976.
17.
Reid, Gladys M. Scurvy: Old Disease - New Insight. Medical Hypotheses, 11, 167-69, 1983.
18.
Miranda, Cristobel L; Henderson, Marilyn C; Reed, Ralph L; Schmitz, John A; Buhler, Donald R. Protective action of zinc against Pyrrolizidine alkaloid-induced hepatotoxicity in rats. Journal of Toxicology and Environmental Health, 2, 359-366, 1982.
19.
Prescott L.F. and Critchley J.A.J.H. The Treatment of Acetaminophen Poisoning. Ann. Rev. Pharmacol. Toxicol., 3, 87-101, 1983.
20.
Jollow D.J., Mitchell J.R., Zampaglione N., and Gillette J.R. Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence of 3,4_bromobenzene oxide as the hepatotoxic metabolite. Pharmacology, 11, 151-69, 2974.
21.
Rechnagel Richard 0. and Glende Eric A.G. Carbon Tetrachloride Hepatotoxicity: An example of lethal cleavage. C.R.C. Critical Reviews in Toxicology, 281, 1973.
22.
Hayashi Y. and L,alichJ.J. Protective Effect of Mercaptoethylamine and Cysteine against Monocrotaline Intoxication in Rats. Toxicol. and Applied Pharmacol., 11, 36-43, 1968.
23.
Hatch Roger C., Clark J. Derrell, Anant V. Jain, Mahaffey Edward A. Experimentally-induced Acute Aflatoxicosis in Goats treated with Ethyl Maleate, Glutathione Precursors, or Thiosulphate. Am. J. Vet. Res., 5, 505-11, 1979.
24.
Burger F.J. Changes in Trace-Element Concentration in the Sera and Hair of Kwashiorkor Patients. In Trace Element Metaboiism in Animals (2), 671-74. Eds. W.G. Hoekstra, J.W. Suttie, H.E. Ganther and W. Mertz. University Park Press, Baltimore, 1974.
406