I
NUTRITIONNOTES
1
Letters to the Editor
Aflatoxin and Oral Contraceptives
Aflatoxin Metabolism and Toxicity
Sir: I have read with the greatest interest the
Sir: The recent review on “Aflatoxin and Oral Contraceptives”’ aptly draws attention to potentially significant interactions between a hazardous food residue and a widely used drug. However, the significant points made miss the focus of the most recent research on this topic. In order to appreciate a potentially significant interaction, a distinction must be made between aflatoxin-induced hepatotoxicity and carcinogenicity. The term “hepatotoxicity” is usually reserved for the acutely toxic effects produced with a single large dose; the term “carcinogenicity” is generally associated with multiple smaller doses such as that observed with traditional ingestion patterns. For these two events, the role of metabolism is exactly opposite, if one assumes it to be rate-limiting in the initiation of these lesions. That is, when mixed function oxidase-dependent metabolism is depressed, acute toxicity is increased but tumor yield is decrea~ed.~z This implies that the parent aflatoxin 61is the acutely toxic agent but that a product of this reaction is the ultimate carcinogen; thus, the 2,3-epoxide is generally accepted as that m e t a b ~ l i t eI. ~ would suggest that a discussion of the relative toxicities of aflatoxin 61 and MI is inappropriate since MI generally accounts for only 1 to 4 percent of the total metabolites and neither its rate of production nor its chemical structure can account for the significant aflatoxin lesions. In any event, the role of mixed function oxidase metabolism is open to question since increased metabolism under one set of experimental conditions (higher dietary protein) increases carcinogenicity, but under a second set of conditions decreases carcinogenicity.5
note on Aflatoxin and Oral Contraceptives published in the May, 1977 issue of Nutrition Reviews.’ We have published two papers in 1974, one in the Recueil de Medicine Veterinaire2 and another in C.R. Acad. Sci. Paris3 concerning the influence of DOT or phenobarbital on aflatoxin intoxication in the duckling. The mechanism of action of those compounds appears perhaps the same as that of oral contraceptives. Further experiments have demonstrated that DDT increases induction of cytochrome P450 if the vitamin A is sufficient in the diet4 Professor R. Ferrando Ecole Nationale Veterinaire Alfort, France
1. Aflatoxin and Oral Contraceptives. Nutrition Reviews 35: 110-111, 1977 2. R. Ferrando, L. N’Diaye, F. Gautier and N. Henry: Effects, Chez le Caneton, de Regimes Renfermant du Tourteau d’Arachide Contenant des Aflatoxines en Association ou Non Avec du DDT ou du Phenobarbital Comparaison Avec un Regime a Base de Soja. Receuil de Medecine Veterinaire 150: 601-606, 1974 3. R. Ferrando, A.L. N’Diaye, N. Henry, C. Fourlon and F. Gautier: Influence d’un Pretraitement du Caneton par le DDT sur sa Reaction Ulterieure vis-a-vis d’un Tourteau d’Arachide Pollue par Aspergillus flavus. C.R. Acad. Sci. Paris 279 (Series D): 1131-1134, 1974 4. R. Ferrando, R. Truhaut, C. Graillot, J-C. Gakand C. Fourlon: Role de la Vitamine A dans I’lnduction du Cytochrome P450 par le DDT. C.R. Acad. Sci. Paris. 279 (Series D) : 999- 1001, 1974 108
NUTRITION REVlEWS / VOL. 35, NO. 7 / J U L Y 1977
The conclusion in the review that “. . . the presence of chemicals like aflatoxin in the diet could enhance or decrease side-effects of the oral contraceptives” may be a valid concern, but it is not suggested by the reports reviewed? quite the opposite results were presented. That is, the effect of an oral contraceptive on aflatoxin acute toxicity and metabolism was studied. From this latter point of view, the usually low levels of aflatoxin BI that might be encountered in certain food commodities would not be expected to exert nearly the effects on enzyme activity as the shifting levels of major nutrient classes such as calories, protein and lipid^.^ Most certainly, the consumption of acutely toxic levels of aflatoxin would seem to have little or no relevance to usage of the pill.
T. Colin Campbell, Ph.D. Professor of Nutritional Biochemistry Cornell University Ithaca, New York 14853
Meeting Announcement
1. Aflatoxin and Oral Contraceptives. Nutrition Reviews 35: 1 10-1 1 1 , 1977 2. T.V. Madhavan and C. Gopolan: Effect of Dietary Protein on Aflatoxin Liver Injury in Weanling Rats. Arch. Path. 88: 123-126,1965 3. T.V. Madhavan and C. Gopolan: The Effect of Dietary Protein on Carcinogenesis of Aflatoxin. Arch. Path. 85: 133-137,1968 4. D.H. Swenson, J.A. Miller and E.C. Miller: 2,3Dihydro-2,3-Dihydroxy-Aflatoxin BI : An Acid Hydrolysis Product of an RNA-Aflatoxin BI Adduct Formed by Hamster and Rat Liver Microsomes In Vitro. Biochem. Biophys. Res. Commun. 53:1 260-1267, 1973 5. A.E. McLean and A. Marshall: Reduced Carcinogenic Effects of Aflatoxin in Rats Given Phenobarbitone. Brit. J. Exp. Path. 52:323-329,1971 6. M.U. Mgbodile and M. Holscher: Studies on Aflatoxin B1 Toxicity in Female Rats Pretreated with an Oral Contraceptive Agent. Food Cosmet. TOX~CO~. 14: 171-174,1976 7. T.C. Campbell and J.R. Hayes: Role of Nutrition in the Drug-Metabolizing Enzyme System. Pharm. Rev. 26: 171-197.1974
of Nutrition Reviews (p. 100). 8. R.A. McCance and E.M. Widdowson: The
The V International Symposium on Ruminant Physiology will be held in Clermont-Ferrand, France, from September 3-7, 1979. The Symposium is sponsored by the French National Institute for Agricultural Research (I.N.R.A.). The Topic for the Symposium will be those aspects of physiology specific to ruminant mode of digestion. For further information contact: Pr. Y. Ruckebusch I.N.R.A. 5e I.S.R.P. 631 10 Beaumont, France
Erratum The following references were missing from the review on “Influence of Intrauterine Nutritional Status on the Development of Obesity in Later Life” which appeared in the May, 1977, issue
Determinants of Growth and Form. Proc. Roy. SOC.Lond. (B) 185:1-17,1974 9. C.A. Smith: Effects of Maternal Undernutrition Upon the Newborn Infant in Holland (19441945).J. Pediat. 30:229-243,1947 10. A. Shukla, H.A. Forsyth, C.M. Anderson and S. M. Marwah: Infantile Overnutrition in the First year of Life. A Field Study in Dudley, Worcestershire. Brit. Med. J. 4:507-515,1972
NOTICE No reprints of the articles in the March, 1977, issue of Nutrition Reviews (The Fifth Annual Marabou Symposium on Food and Fiber) are available. We also wish to emphasize that reprints of the signed articles in Nutrition Reviews, usually the article at the beginning of each issue, may be available from the author of the article. They are not available from Nutrition Reviews nor are reprints of unsigned reviews ever available. N u r R i r i o N R E V I E W S V O L . 35, NO. 7 I JULY 1977
189
NUTRITIONNOTES
1
Letters to the Editor
Aflatoxin and Oral Contraceptives
Aflatoxin Metabolism and Toxicity
Sir: I have read with the greatest interest the
Sir: The recent review on “Aflatoxin and Oral Contraceptives”’ aptly draws attention to potentially significant interactions between a hazardous food residue and a widely used drug. However, the significant points made miss the focus of the most recent research on this topic. In order to appreciate a potentially significant interaction, a distinction must be made between aflatoxin-induced hepatotoxicity and carcinogenicity. The term “hepatotoxicity” is usually reserved for the acutely toxic effects produced with a single large dose; the term “carcinogenicity” is generally associated with multiple smaller doses such as that observed with traditional ingestion patterns. For these two events, the role of metabolism is exactly opposite, if one assumes it to be rate-limiting in the initiation of these lesions. That is, when mixed function oxidase-dependent metabolism is depressed, acute toxicity is increased but tumor yield is decrea~ed.~z This implies that the parent aflatoxin 61is the acutely toxic agent but that a product of this reaction is the ultimate carcinogen; thus, the 2,3-epoxide is generally accepted as that m e t a b ~ l i t eI. ~ would suggest that a discussion of the relative toxicities of aflatoxin 61 and MI is inappropriate since MI generally accounts for only 1 to 4 percent of the total metabolites and neither its rate of production nor its chemical structure can account for the significant aflatoxin lesions. In any event, the role of mixed function oxidase metabolism is open to question since increased metabolism under one set of experimental conditions (higher dietary protein) increases carcinogenicity, but under a second set of conditions decreases carcinogenicity.5
note on Aflatoxin and Oral Contraceptives published in the May, 1977 issue of Nutrition Reviews.’ We have published two papers in 1974, one in the Recueil de Medicine Veterinaire2 and another in C.R. Acad. Sci. Paris3 concerning the influence of DOT or phenobarbital on aflatoxin intoxication in the duckling. The mechanism of action of those compounds appears perhaps the same as that of oral contraceptives. Further experiments have demonstrated that DDT increases induction of cytochrome P450 if the vitamin A is sufficient in the diet4 Professor R. Ferrando Ecole Nationale Veterinaire Alfort, France
1. Aflatoxin and Oral Contraceptives. Nutrition Reviews 35: 110-111, 1977 2. R. Ferrando, L. N’Diaye, F. Gautier and N. Henry: Effects, Chez le Caneton, de Regimes Renfermant du Tourteau d’Arachide Contenant des Aflatoxines en Association ou Non Avec du DDT ou du Phenobarbital Comparaison Avec un Regime a Base de Soja. Receuil de Medecine Veterinaire 150: 601-606, 1974 3. R. Ferrando, A.L. N’Diaye, N. Henry, C. Fourlon and F. Gautier: Influence d’un Pretraitement du Caneton par le DDT sur sa Reaction Ulterieure vis-a-vis d’un Tourteau d’Arachide Pollue par Aspergillus flavus. C.R. Acad. Sci. Paris 279 (Series D): 1131-1134, 1974 4. R. Ferrando, R. Truhaut, C. Graillot, J-C. Gakand C. Fourlon: Role de la Vitamine A dans I’lnduction du Cytochrome P450 par le DDT. C.R. Acad. Sci. Paris. 279 (Series D) : 999- 1001, 1974 108
NUTRITION REVlEWS / VOL. 35, NO. 7 / J U L Y 1977
The conclusion in the review that “. . . the presence of chemicals like aflatoxin in the diet could enhance or decrease side-effects of the oral contraceptives” may be a valid concern, but it is not suggested by the reports reviewed? quite the opposite results were presented. That is, the effect of an oral contraceptive on aflatoxin acute toxicity and metabolism was studied. From this latter point of view, the usually low levels of aflatoxin BI that might be encountered in certain food commodities would not be expected to exert nearly the effects on enzyme activity as the shifting levels of major nutrient classes such as calories, protein and lipid^.^ Most certainly, the consumption of acutely toxic levels of aflatoxin would seem to have little or no relevance to usage of the pill.
T. Colin Campbell, Ph.D. Professor of Nutritional Biochemistry Cornell University Ithaca, New York 14853
Meeting Announcement
1. Aflatoxin and Oral Contraceptives. Nutrition Reviews 35: 1 10-1 1 1 , 1977 2. T.V. Madhavan and C. Gopolan: Effect of Dietary Protein on Aflatoxin Liver Injury in Weanling Rats. Arch. Path. 88: 123-126,1965 3. T.V. Madhavan and C. Gopolan: The Effect of Dietary Protein on Carcinogenesis of Aflatoxin. Arch. Path. 85: 133-137,1968 4. D.H. Swenson, J.A. Miller and E.C. Miller: 2,3Dihydro-2,3-Dihydroxy-Aflatoxin BI : An Acid Hydrolysis Product of an RNA-Aflatoxin BI Adduct Formed by Hamster and Rat Liver Microsomes In Vitro. Biochem. Biophys. Res. Commun. 53:1 260-1267, 1973 5. A.E. McLean and A. Marshall: Reduced Carcinogenic Effects of Aflatoxin in Rats Given Phenobarbitone. Brit. J. Exp. Path. 52:323-329,1971 6. M.U. Mgbodile and M. Holscher: Studies on Aflatoxin B1 Toxicity in Female Rats Pretreated with an Oral Contraceptive Agent. Food Cosmet. TOX~CO~. 14: 171-174,1976 7. T.C. Campbell and J.R. Hayes: Role of Nutrition in the Drug-Metabolizing Enzyme System. Pharm. Rev. 26: 171-197.1974
of Nutrition Reviews (p. 100). 8. R.A. McCance and E.M. Widdowson: The
The V International Symposium on Ruminant Physiology will be held in Clermont-Ferrand, France, from September 3-7, 1979. The Symposium is sponsored by the French National Institute for Agricultural Research (I.N.R.A.). The Topic for the Symposium will be those aspects of physiology specific to ruminant mode of digestion. For further information contact: Pr. Y. Ruckebusch I.N.R.A. 5e I.S.R.P. 631 10 Beaumont, France
Erratum The following references were missing from the review on “Influence of Intrauterine Nutritional Status on the Development of Obesity in Later Life” which appeared in the May, 1977, issue
Determinants of Growth and Form. Proc. Roy. SOC.Lond. (B) 185:1-17,1974 9. C.A. Smith: Effects of Maternal Undernutrition Upon the Newborn Infant in Holland (19441945).J. Pediat. 30:229-243,1947 10. A. Shukla, H.A. Forsyth, C.M. Anderson and S. M. Marwah: Infantile Overnutrition in the First year of Life. A Field Study in Dudley, Worcestershire. Brit. Med. J. 4:507-515,1972
NOTICE No reprints of the articles in the March, 1977, issue of Nutrition Reviews (The Fifth Annual Marabou Symposium on Food and Fiber) are available. We also wish to emphasize that reprints of the signed articles in Nutrition Reviews, usually the article at the beginning of each issue, may be available from the author of the article. They are not available from Nutrition Reviews nor are reprints of unsigned reviews ever available. N u r R i r i o N R E V I E W S V O L . 35, NO. 7 I JULY 1977
189
