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Fetal Drug Metabolism and Its Possible Clinical Implications

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  • Clinical Pharmacokinetic Concepts
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Summary

The ability of the human conceptus to metabolise xenobiotics during early gestation is now well established. Specific activities of liver enzymes have been demonstrated to exist in the late embryonic phase for numerous cytochrome P450 monooxygenases and many phase II enzymes such as glutathione-, N-acetyl-, sulpho- and uridine diphosphate-glucuronosyltransferase. As in the adult, fetal drug metabolism may function in a dual manner, either as a protective mechanism against chemical aggression when transforming active molecules into inactive ones, or as a toxifying system when transforming innocuous compounds into reactive metabolites. Recent advances in the understanding of enzyme variabilities at molecular and functional levels illustrate the necessity of studying these variations in the human fetus as well as in adults, since the combination of genetic, developmental and environmental factors seem to control fetal enzyme activities and ultimately determine the variability in individual susceptibility to chemicals in utero. Despite the scarcity of well documented cases of adverse fetal reactions resulting directly from metabolic toxicity, the clinical relevance of the potential role of biotransformation in generating fetal toxicity is a strong appeal to promote further studies dealing with the ontogeny of drug-metabolising capacity and its regulation.

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References

  • Abraham NG, Lin JH, Mitrione SM, Schwartzman ML, Levere RD, et al. Expression of heme oxygenase gene in rat and human liver. Biochemical and Biophysical Research Communications 150: 717–722, 1988

    Article  PubMed  CAS  Google Scholar 

  • Aranda JV, Clozel M. Effets pharmacologiques de la caféine et de la théophylline chez le prématuré. Developmental Pharmacology and Therapeutics 4: 165–172, 1982

    PubMed  Google Scholar 

  • Aranda JV, Louridas AT, Vitullo BB, Thorn P, Aldridge A, et al. Metabolism of theophylline to caffeine in human fetal liver. Science 206: 1319–1321, 1979

    Article  PubMed  CAS  Google Scholar 

  • Brashear WT, Kuhnert BR, Wei R. Maternal and neonatal urinary excretion of sulfate and glucuronide ritodrine conjugates. Clinical Pharmacology and Therapeutics 44: 634–641, 1988

    Article  PubMed  CAS  Google Scholar 

  • Buehler BA. Epoxide hydrolase activity in fibroblasts: correlation with clinical features of the fetal hydantoin syndrome. Proceedings of the Greenwood Genetic Center 6: 117, 1987

    Google Scholar 

  • Burchell B. UDP-glucuronyltransferase activity towards oestriol in fresh and cultured foetal tissues from man and other species. Journal of Steroid Biochemistry 5: 261–267, 1974

    Article  PubMed  CAS  Google Scholar 

  • Bustamante SA, Stumpff LC. Fetal hydantoin syndrome in triplets. American Journal of Disease of Children 132: 978–979, 1978

    CAS  Google Scholar 

  • Chernoff GF. The fetal alcohol syndrome in mice: an animal model. Teratology 15: 223–229, 1977

    Article  PubMed  CAS  Google Scholar 

  • Chung LWK, Chao H. Neonatal imprinting and hepatic cytochrome P-450: I. Comparison of testosterone hydroxylation between neonatally imprinted and non imprinted rats. Molecular Pharmacology 18: 543–549, 1980

    PubMed  CAS  Google Scholar 

  • Chung LWK, Raymond G, Fox S. Role of neonatal androgen in the development of hepatic microsomal drug metabolizing enzymes. Journal of Pharmacology and Experimental Therapeutics 193: 621–630, 1975

    PubMed  CAS  Google Scholar 

  • Cresteil T, Beaune P, Kremers P, Celier C, Guengerich FP, et al. Immunoquantification of epoxide hydrolase and cytochrome P-450 isozymes in fetal and adult liver microsomes. European Journal of Biochemistry 151: 345–350, 1985

    Article  PubMed  CAS  Google Scholar 

  • Cresteil T, Beaune P, Kremers P, Flinois JP, Leroux JP. Drug-metabolizing enzymes in human foetal liver: partial resolution of multiple cytochromes P450. Pediatric Pharmacology 2: 199–207, 1982

    PubMed  CAS  Google Scholar 

  • Danpure CJ, Jennings PR, Penketh RJ, Wise P, Cooper PJ, et al. Fetal liver alanine: glyoxylate aminotransferase and the prenatal diagnosis of primary hyperoxaluria type I. Prenatal Diagnosis 9: 271–281, 1989

    Article  PubMed  CAS  Google Scholar 

  • Danpure CJ, Jennings PR, Watts RWE. Enzymological diagnosis of primary hyperoxyluria type I by measurment of hepatic alanine: glyoxylate aminotransferase activity. Lancet I: 289–291, 1987

    Article  Google Scholar 

  • Dayer P, Leemann T, Striberni R. Dextromethorphan O-demethylation in liver microsomes as a prototype reaction to monitor cytochrome P-450 db1 activity. Clinical Pharmacology and Therapeutics 45: 34–40, 1989

    Article  PubMed  CAS  Google Scholar 

  • Dutton GJ. Glucuronide synthesis in foetal liver and other tissues. Biochemical Journal 71: 141–148, 1959

    PubMed  CAS  Google Scholar 

  • Fouts JR, Adamson RH. Drug metabolism in the newborn rabbit. Science 129: 897–898, 1959

    Article  PubMed  CAS  Google Scholar 

  • Fox J, Hack AM, Fenton WA, Golbus MS, Winter S, et al. Prenatal diagnosis of ornithine transcarbamylase deficiency with the use of DNA polymorphisms. New England Journal of Medicine 315: 1205–1208, 1986

    Article  PubMed  CAS  Google Scholar 

  • Gardner MJ, Snee MP, Hall AJ, Powell CA, Downes S, et al. Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. British Medical Journal 300: 423–429, 1990

    Article  PubMed  CAS  Google Scholar 

  • Gawronska-Sklarz B, Swensson JO, Widen J, Rane A. Differential hepatic glucuronidation of (−) and (+)-morphine in the rat and the human fetus. In Matern et al. (Eds) Advances in glucuronide conjugation, pp. 335–340, MTP Press, Lancaster, 1985

    Google Scholar 

  • Golbus MS, Simpson TJ, Koresawa M, Appelman Z, Alpers CE. The prenatal determination of glucose-6 phosphatase activity by fetal liver biopsy. Prenatal Diagnosis 8: 401–404, 1988

    Article  PubMed  CAS  Google Scholar 

  • Holzgreve W, Golbus MS. Prenatal diagnosis of orthinine transcarbamylase deficiency utilising fetal liver biopsy. American Journal of Human Genetics 36: 320–328, 1984

    PubMed  CAS  Google Scholar 

  • Ioannides C, Parke DV. The cytochromes P-448 — a unique family of enzymes involved in chemical toxicity and carcinogenesis. Biochemical Pharmacology 36: 4197–4207, 1987

    Article  PubMed  CAS  Google Scholar 

  • Jondorf WR, Maickel RP, Brodie BB. Inability of newborn mice and guinea pigs to metabolize drugs. Biochemical Pharmacology 1: 352–354, 1958

    Article  Google Scholar 

  • Jones KL, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. New England Journal of Medicine 320: 1661–1666, 1989

    Article  PubMed  CAS  Google Scholar 

  • Juchau MR, Chao ST, Omiecinski CJ. Drug metabolism by the human fetus. Clinical Pharmacokinetics 5: 320–339, 1980

    Article  PubMed  CAS  Google Scholar 

  • Kawade N, Onishi S. The prenatal and postnatal development of UDP-glucuronosyltransferase activity towards bilirubin and the effect of premature birth on this activity in the human liver. Biochemical Journal 196: 257–260, 1981

    PubMed  CAS  Google Scholar 

  • Krauer B, Krauer F. Drug kinetics in pregnancy. Clinical Pharmacokinetics 2: 167–181, 1977

    Article  PubMed  CAS  Google Scholar 

  • Krauer B, Krauer F, Hytten FE. Drug disposition and pharmacokinetics in the maternal-placental-fetal unit. Pharmacology and Therapeutics 10: 301–328, 1980

    Article  PubMed  CAS  Google Scholar 

  • Kronbach T, Mathys D, Umeno M, Gonzalez FJ, Meyer UA. Oxidation of midazolam and triazolam by human liver cytochrome P450 IIIA4. Molecular Pharmacology 36: 89–96, 1989

    PubMed  CAS  Google Scholar 

  • Ladona MG, Park SS, Gelboin HV, Hammar L, Rane A. Monoclonal antibody directed detection of cytochrome P-450 (PCN) in human fetal liver. Biochemical Pharmacology 37: 4735–4741, 1988

    Article  PubMed  CAS  Google Scholar 

  • Leakey JEA, Hume R, Burchell B. Development of multiple activities of UDP-glucuronosyltransferase in human liver. Biochemical Journal 245: 859–861, 1987

    Google Scholar 

  • Leemann T, Dayer P, Meyer UA. Single dose quinidine treatment inhibits metoprolol oxidation in extensive metabolizers. European Journal of Clinical Pharmacology 29: 739–741, 1986

    Article  PubMed  CAS  Google Scholar 

  • Lieber CS. Biochemical and molecular basis of alcohol-induced injury to liver and other tissues. New England Journal of Medicine 319: 1639–1650, 1988

    Article  PubMed  CAS  Google Scholar 

  • Liggins GC. Prenatal glucocorticoid treatment: prevention of respiratory distress syndrome. In Moore (Ed.) Lung maturation and prevention of hyaline membrane disease. 70th Ross Conference on Pediatric Research, pp. 97–103, Ross Laboratories, Columbus, 1976

    Google Scholar 

  • Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for the prevention of the respiratory distress syndrome in premature infants. Pediatrics 50: 515–525, 1972

    PubMed  CAS  Google Scholar 

  • Mathis JM, Prough RA, Simpson ER. Synergistic induction of monooxygenase activity by glucocorticoids and polycyclic aromatic hydrocarbons in human fetal hepatocytes in primary monolayer culture. Archives of Biochemistry and Biophysics 244: 650–661, 1986

    Article  PubMed  CAS  Google Scholar 

  • Mattison DR, Kozlowski K, Quirk JG, Jelovsek FR. Effects of drugs and chemicals on the fetus: Part I. Determining teratogenic risk. Contemporary Ob/Gyn 33: 163–176, 1989

    Google Scholar 

  • Maurer HM, Wolff JA, Finster M, Poppers PJ, Pantuck E, et al. Reduction in concentration of total serum bilirubin in offspring of women treated with phenobarbitone during pregnancy. Lancet 2: 122–124, 1968

    Article  PubMed  CAS  Google Scholar 

  • Meisel M, Schneider T, Siegmund W, Nikschick S, Kebingat KJ, et al. Development of human polymorphic N-acetyltransferase. Biological Research in Pregnancy and Perinatology 7: 74–76, 1986

    PubMed  CAS  Google Scholar 

  • Meyer UA. Molecular genetics and the future of pharmacogenetics. Pharmacology and Therapeutics 46: 349–355, 1990

    Article  PubMed  CAS  Google Scholar 

  • Mucklow JC. Environmental factors affecting drug metabolism. Pharmacology and Therapeutics 36: 105–117, 1988

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW. Possible clinical importance of genetic differences in drug metabolism. British Medical Journal 283: 537–542, 1981

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW, Adesnik M, Coon MJ, Estabrook RW, Gonzalez FJ, et al. The P450 gene superfamily: recommended nomenclature. DNA 6: 1–11, 1987

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW, Bigelow SW. Genetic control of drug metabolism: relationship to birth defects. Seminars in Perinatology 6: 105–115, 1982

    PubMed  CAS  Google Scholar 

  • Nebert DW, Eisen JJ, Negishi M, Lang MA, Hjelmeland LM, et al. Genetic mechanism controlling the induction of polysubstrate monooxygenase (P-450) activities. Annual Review of Pharmacology and Toxicology 21: 431–462, 1981

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW, Negishi M. Multiple forms of cytochrome P450 and the importance of molecular biology and evolution. Biochemical Pharmacology 31: 2311–2317, 1982

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, et al. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature for the chromosomal loci. DNA and Cell Biology 10: 1–14, 1991

    Article  PubMed  CAS  Google Scholar 

  • Nebert DW, Nelson DR, Feyereisen R. Evolution of the cytochrome P450 genes. Xenobiotica 10: 1149–1160, 1989

    Article  Google Scholar 

  • Neims AH, Warner M, Loughnan PM, Aranda JV. Developmental aspects of the hepatic P-450 monooxygenase system. Annual Review of Pharmacology and Toxicology 16: 427–445, 1976

    Article  PubMed  CAS  Google Scholar 

  • Netter KJ. Comparison of fetal and adult drug metabolising enzymes. In Benford et al. (Eds) Drug metabolism from molecules to man, pp. 319–329, Taylor & Francis, London, 1987

    Google Scholar 

  • Pacifici GM, Bencici C, Rane A. Acetyltransferase in humans: development and tissue distribution. Pharmacology 32: 283–291, 1986

    Article  PubMed  CAS  Google Scholar 

  • Pacifici GM, Franchi M, Guiliani L, Rane A. Development of the glucuronyltransferase and sulphotransferase towards 2-naphthol in human fetus. Developmental Pharmacology and Therapeutics 14: 108–114, 1990

    CAS  Google Scholar 

  • Pacifici GM, Rane A. Metabolism of sytrene oxide in different human fetal tissues. Drug Metabolism and Disposition 10: 302–305, 1982

    PubMed  CAS  Google Scholar 

  • Paré (1575). Les oeuvres d’Ambroise Paré, 10th ed., Book 25, chapt. VIII, p. 656, 1641

  • Parke DV, Ioannides C, Lewis DFV. Metabolic activation of carcinogens and toxic chemicals. Human Toxicology 7: 397–404, 1988

    Article  PubMed  CAS  Google Scholar 

  • Pelkonen O. Biotransformation of xenobiotics isn the fetus. Pharmacology and Therapeutics 10: 261–281, 1980

    Article  PubMed  CAS  Google Scholar 

  • Pelkonen O, Pasanen M, Vahakangas K. Metabolic activation by the fetus and placenta. In Benford et al. (Eds) Drug metabolism from molecules to man, pp. 734–746, Taylor & Francis, London, 1987

    Google Scholar 

  • Pelkonen O, Vorne M, Jouppila P, Kärki NT. Metabolism of chlorpromazine and p-nitrobenzoic acid in the liver, intestine and kidney of the human foetus. Acta Pharmacologica et Toxicologica 29: 284–294, 1971

    Article  PubMed  CAS  Google Scholar 

  • Pembrey ME, Old JM, Leonard JV, Rodeck CH, Warren R, et al. Prenatal diagnosis of ornithine carbamoyl transferase deficiency using a gene specific probe. Journal of Medical Genetics 22: 462–465, 1985

    Article  PubMed  CAS  Google Scholar 

  • Peng DR, Pacifici GM, Rane A. Human fetal liver cultures: basal activities and inducibility of epoxide hydrolases and aryl hydrocarbon hydroxylase. Biochemical Pharmacology 33: 71–77, 1984

    Article  PubMed  CAS  Google Scholar 

  • Phelan MC, Pellock JM, Nance WE. Discordant expression of fetal hydantoin syndrome in heteropaternal dizygotic twins. New England Journal of Medicine 307: 99–101, 1982

    Article  PubMed  CAS  Google Scholar 

  • Pollard I, Smallshaw J. Male mediated caffeine effects over two generations of rats. Journal of Developmental Physiology 10: 271–281, 1988

    PubMed  CAS  Google Scholar 

  • Rane A, Ackermann E. Metabolism of ethylmorphine and aniline in human fetal liver. Clinical Pharmacology and Therapeutics 13: 663–670, 1972

    PubMed  CAS  Google Scholar 

  • Rane A, Tomson G. Prenatal and neonatal drug metabolism in man. European Journal of Clinical Pharmacology 18: 9–15, 1980

    Article  PubMed  CAS  Google Scholar 

  • Rettie AE, Rettenmeier AW, Beyer BK, Baillie TA, Juchau MR. Valproate hydroxylation by human fetal tissues and embryotoxicity of metabolites. Clinical Pharmacology and Therapeutics 40: 172–177, 1986

    Article  PubMed  CAS  Google Scholar 

  • Rodeck CH, Patrick AD, Pembrey ME, Tzannatos C, Whitfield AE. Fetal liver biopsy for prenatal diagnosis of ornithine carbamyl transferase deficiency. Lancet 2: 297–300, 1982

    Article  PubMed  CAS  Google Scholar 

  • Simpson VJ, Zhau HE, Runner MR, Chung LWK. Coordinated maternal imprinting and paternal genotype determined the ultimate level of hepatic cytochrome P-450 and associated monooxygenase activities. Drug Metabolism and Disposition 16: 576–581, 1988

    PubMed  CAS  Google Scholar 

  • Smith RC. Polymorphism in drug metabolism: implications for drug toxicity. Archives of Toxicology (Suppl. 9): 138–146, 1986

    Google Scholar 

  • Sonawane BR, Yaffe SJ. Drug and chemical action in pregnancy: pharmacologic and toxicologic principles, p. 103, Marcel Dekker, New York, 1986

    Google Scholar 

  • Soyka LF, Bigelow SW. Drug-metabolizing enzymes and their activity in the human fetus. In Stern (Ed.) Drug use in pregnancy, pp. 17–44, Adis Health Science Press, Sydney, 1984

    Google Scholar 

  • Soyka LF, Deckert FW. Further studies on the inhibition of drug metabolism by pregnanolone and related steroids. Biochemical Pharmacology 23: 1629, 1974

    Article  PubMed  CAS  Google Scholar 

  • Spielberg SP. Pharmacogenetics and teratology. In Krauer et al. (Eds) Drugs and pregnancy: maternal drug handling — fetal drug exposure, pp. 85–99, Academic Press, London, 1984

    Google Scholar 

  • Spielberg SP, Gordon GB, Beake DA, Goldstein DA, Herlong HF. Predisposition to phenytoin hepatotoxicity assessed in vitro. New England Journal of Medicine 305: 722–727, 1981

    Article  PubMed  CAS  Google Scholar 

  • Stern L, Khanna NR, Levy G, Yaffe SJ. Effect of phenobarbital on hyperbilirubinemia and glucuronide formation in newborns. American Journal of Diseases of Children 120: 26, 1970

    PubMed  CAS  Google Scholar 

  • Strickler SM, Miller MA, Andermann E, Dansky LV, Seni MH, et al. Genetic predisposition to phenytoin induced birth defects. Lancet 2: 746, 1985

    Article  PubMed  CAS  Google Scholar 

  • Thurman RG, Handler JA. New perspectives in catalase dependent ethanol metabolism. Drug Metabolism Reviews 20: 679–688, 1989

    Article  PubMed  CAS  Google Scholar 

  • Vesell ES. Genetic and environmental factors affecting drug disposition in man. Clinical Pharmacology and Therapeutics 22: 659–679, 1977

    PubMed  CAS  Google Scholar 

  • Vesell ES, Passananti GT. Genetic and environmental factors affecting host response to drugs and other chemical compounds in our environment. Environmental Health Perspectives 20: 159–182, 1977

    Article  PubMed  CAS  Google Scholar 

  • Yaffe SJ, Rane A, Sjöqvist F, Boréus LO, Orrenius S. The presence of a monooxygenase system in human fetal liver microsomes. Life Sciences 9: 1189–1200, 1970

    Article  CAS  Google Scholar 

  • Yue QY, Bertilsson L, Dahe-Puustinen ML, Säwe J, Sjöqvist F, et al. Disassociation between debrisoquine hydroxylation phenotype and genotype among Chinese. Lancet 2: 870, 1989

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Obstetrics and Gynaecology, University Hospital, CH 1211, Geneva 4, Switzerland

    Béatrice Krauer & Pierre Dayer

  2. Department of Medicine, University Hospital, Geneva, Switzerland

    Béatrice Krauer & Pierre Dayer

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  1. Béatrice Krauer
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  2. Pierre Dayer
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Krauer, B., Dayer, P. Fetal Drug Metabolism and Its Possible Clinical Implications. Clin. Pharmacokinet. 21, 70–80 (1991). https://doi.org/10.2165/00003088-199121010-00005

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