Formation of Toxic Intermediates in Fetal Tissues

  • Olavi Pelkonen


Pharmacological actions and toxic effects of drugs and other foreign compounds are often mediated by metabolites of the administered compounds rather than by the unchanged compounds themselves. For example, bromobenzene and other halogenated hydrocarbons are converted to reactive epoxides by the action of a drug-oxidizing monooxygenase system in the liver and other tissues, with resultant liver injury (1,2). Most carcinogenic substances, e.g., acetaminofluorene and polycyclic aromatic hydrocarbons, are not carcinogenic per se, but have to be transformed into reactive electrophiles, which attack critical target molecules, thus initiating carcinogenesis (3). Many halogenated hydrocarbon pesticides are converted by microsomal enzymes into epoxides, which generally are more toxic than the parent compounds. These examples point to the considerable importance of drug-oxidizing enzyme systems in the toxic effects of xenobiotics.


Polycyclic Aromatic Hydrocarbon Fetal Liver Fetal Tissue Polycyclic Hydrocarbon Fetal Liver Cell 
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  1. 1.
    J. R. Gillette, A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. I. Correlation of changes in covalent binding of reactive metabolites with changes in the incidence and severity of toxicity, Biochem. Pharmacol. 23, 2785–2794 (1974).PubMedCrossRefGoogle Scholar
  2. 2.
    J. R. Gillette, A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity. II. Alterations in the kinetics of covalent binding, Biochem. Pharmacol. 23, 2927–2938 (1974).PubMedCrossRefGoogle Scholar
  3. 3.
    J. A. Miller, Carcinogenesis by chemicals: An overview, Cancer Res. 30, 559–576 (1970).PubMedGoogle Scholar
  4. 4.
    A. Rane, C. V. Bahr, S, Orrenius, and F. Sjöqvist, in: Fetal Pharmacology (L. Boreus, ed.), pp. 287–301, Raven Press, New York (1973).Google Scholar
  5. 5.
    A. Rane, F. Sjöqvist, and S. Orrenius, Drugs and fetal metabolism, Clin. Pharmacol. Ther. 14, 666–672 (1973).PubMedGoogle Scholar
  6. 6.
    M. R. Juchau, Q. H. Lee, G. L. Louviaux, K. G. Symms, J. Krasner, and S. J. Yaffe, in: Fetal Pharmacology ( L. Boreus, ed.), pp. 321–333, Raven Press, New York (1973).Google Scholar
  7. 7.
    O. Pelkonen and N. T. Kärki, Drug metabolism in human fetal tissues, Life Sci. 13, 1163–1180 (1973).CrossRefGoogle Scholar
  8. 8.
    O. Pelkonen, P. Korhonen, P. Jouppila, and N. T. Kärki, in: Basic and Therapeutic Aspects of Perinatal Pharmacology ( P. L. Morselli, S. Garattini, and F. Sereni, eds.), pp. 65–74, Raven Press, New York (1975).Google Scholar
  9. 9.
    O. Pelkonen, Transplacental transfer of foreign compounds and their metabolism by the foetus, in: Progress in Drug Metabolism, Vol. 2 (L. F. Chasseaud and J. W. Bridges, eds.), in press, ChichesterGoogle Scholar
  10. 10.
    O. Pelkonen, E. H. Kaltiala, T. K. I. Larmi, and N. T. Kärki, Comparison of activities of drug-metabolizing enzymes in human fetal and adult livers, Clin. Pharmacol. Ther. 14, 840–846 (1973).PubMedGoogle Scholar
  11. 11.
    S. S. Thorgeirsson, Mechanism of hepatic drug oxidation and its relationship to individual differences in rates of oxidation in man, Ph.D. thesis, University of London (1972).Google Scholar
  12. 12.
    O. Pelkonen, P. Arvela, and N. T. Kärki, 3,4-Benzpyrene and N rnethylaniline metabolizing enzymes in the immature human foetus and placenta, Acta Pharmacol. Toxicol. 30, 385–395 (1971).CrossRefGoogle Scholar
  13. 13.
    O. Pelkonen, M. Vorne, P. Jouppila, and N. T. Kärki, Metabolism of chlorpromazine and p-nitrobenzoic acid in the liver, intestine and kidney of the human foetus, Acta Pharmacol. Toxicol. 29, 284–294 (1971).CrossRefGoogle Scholar
  14. 14.
    A. Rane and E. Ackermann, Metabolism of ethylmorphine and aniline in human fetal liver, Clin. Pharmacol. Ther. 13, 663–670 (1972).PubMedGoogle Scholar
  15. 15.
    A. B. Rifkind, S. Bennett, E. S. Forster, and N. I. New, Components of the heure biosynthetic pathway and mixed function oxidase activity in human fetal tissues, Biochem. Pharmacol. 24, 839–846 (1975).PubMedCrossRefGoogle Scholar
  16. 16.
    O. Pelkonen, Developmental change in the apparent kinetic properties of drug-oxidizing enzymes in the human liver, Res. Commun. Chem. Pathol. Pharmacol 10, 293–302 (1975).Google Scholar
  17. 17.
    O. Pelkonen and N. T. Kärki, 3,4-Benzpyrene and aniline are hydroxylated by human fetal liver but not placenta at 6–7 weeks of fetal age, Biochem. Pharmacol. 22, 1538–1540 (1973).PubMedCrossRefGoogle Scholar
  18. 18.
    L. Zamboni, Electron microscopic studies of blood embryogenesis in humans. I. The ultrastructure of the fetal liver, J. Ultrastruct. Res 12, 509–524 (1965).PubMedCrossRefGoogle Scholar
  19. 19.
    O. Pelkonen, Drug metabolism in the human fetal liver: Relationship to fetal age, Arch. Int. Pharmacodyn. Ther. 202, 281–287 (1973).PubMedGoogle Scholar
  20. 20.
    M. R. Juchau, M. G. Pedersen, and K. G. Symms, Hydroxylation of 3,4-benzpyrene in human fetal tissue homogenates, Biochem. Pharmacol 21, 2269–2272 (1972).PubMedCrossRefGoogle Scholar
  21. 21.
    R. M. Welch, Y. E. Harrison, A. H. Conney, P. J. Poppers, and M. Finster, Cigarette smoking: Stimulatory effect on metabolism of 3,4-benzpyrene by enzymes in human placenta, Science 160, 541–542 (1968).PubMedCrossRefGoogle Scholar
  22. 22.
    M. R. Juchau, Human placental hydroxylation of 3,4-benzpyrene during early gestation and at term, ToxicoL Appl. Pharmacol 18, 665–675 (1971).PubMedCrossRefGoogle Scholar
  23. 23.
    D. W. Nebert, J. R. Robinson, A. Niwa, K. Kumaki, and A. P. Poland, Genetic expression of aryl hydrocarbon hydroxylase activity in the mouse, J. Cell. PhysioL 85, 393–414 (1975).PubMedCrossRefGoogle Scholar
  24. 24.
    R. E. Rasmussen and I. Y. Wang, Dependence of specific metabolism of benzo[a] pyrene on the inducer of hydroxylase activity, Cancer Res. 34, 2290–2295 (1974).PubMedGoogle Scholar
  25. 25.
    F. M. Goujon, D. W. Nebert, and J. E. Gielen, Genetic expression of aryl hydrocarbon hydroxylase induction. IV. Interaction of various compounds with different forms of cytochrome P-450 and the effect on benzo[a] pyrene metabolism in vitro, Mol. Pharmacol. 8, 667–680 (1972).PubMedGoogle Scholar
  26. 26.
    E. Schiede and H.-J. Merker, Effect of benzo[a]pyrene treatment on the benzo[a]pyrene hydroxylase activity in maternal liver, placenta, and fetus of the rat during day 13 to day 18 of gestation, Arch. Pharmacol. 272, 89–100 (1972).CrossRefGoogle Scholar
  27. 27.
    O. Pelkonen, P. Jouppila, and N. T. Kärki, Effect of maternal cigarette smoking on 3,4-benzpyrene and N-methylaniline metabolism in human fetal liver and placenta, Toxicol. Appl. Pharmacol 23, 399–407 (1972).PubMedCrossRefGoogle Scholar
  28. 28.
    O. Pelkonen, P. Jouppila, E. H. Kaltiala, and N. T. Kârki, in: Developmental and Genetic Aspects of Drug and Environmental Toxicity (W. A. M. Duncan, ed.), International Congress Series No. 345, pp. 154–158, Excerpta Medica, Amsterdam (1975).Google Scholar
  29. 29.
    R. M. Welch, B. Gommi, A. P. Alvares, and A. H. Conney, Effect of enzyme induction on the metabolism of benzo[a] pyrene and 3’-monomethylaminoazobenzene in the pregnant and fetal rat, Cancer Res. 32, 973–978 (1972).PubMedGoogle Scholar
  30. 30.
    M. R. Juchau and M. G. Pedersen, Drug biotransformation reactions in the human fetal adrenal gland, Life Sci. 12 (II), 193–204 (1973).CrossRefGoogle Scholar
  31. 31.
    O. Pelkonen, P. Korhonen, P. Jouppila, and N. T. Kârki, Induction of aryl hydrocarbon hydroxylase is stimulated in human lymphocytes by mitogens and benz [a] anthracene, bons, Life Sci. 16, 1403–1410 (1975).PubMedCrossRefGoogle Scholar
  32. 32.
    J. P. Whitlock, H. L. Cooper, and H. V. Gelboin, Aryl hydrocarbon (benzopyrene) hydroxylase is stimulated in human lymphocytes by mitogens and benz[a] anthracene, Science 177, 618–619 (1972).PubMedCrossRefGoogle Scholar
  33. 33.
    D. L. Busbee, C. R. Shaw, and E. T. Cantrell, Aryl hydrocarbon hydroxylase induction in human lymphocytes, Science 178, 315–317 (1972).PubMedCrossRefGoogle Scholar
  34. 34.
    A. P. Alvares, A. Kappas, W. Levin, and A. H. Conney, Inducibility of benzo[a] pyrene hydroxylase in human skin by polycyclic hydrocarbons, Clin. Pharmacol. Ther. 14, 30–40 (1973).PubMedGoogle Scholar
  35. 35.
    G. Kellermann, M. Luyten-Kellermann, and C. R. Shaw, Metabolism of polycyclic aromatic hydrocarbons in cultured human leukocytes under genetic control, Humangenetik 20, 257–263 (1973).PubMedCrossRefGoogle Scholar
  36. 36.
    P. Sims, Qualitative and quantitative studies on the metabolism of a series of aromatic hydrocarbons by rat-liver preparations, Biochem. Pharmacol 19, 795–818 (1970).PubMedCrossRefGoogle Scholar
  37. 37.
    A. Borgen, H. Darvey, N. Castagnoli, T. T. Crocker, R. E. Rasmussen, and I. Y. Wang, Metabolic conversion of benzo[a]pyrene by Syrian hamster liver microsomes and binding of metabolites to deozyribonucleic acid, J. Med. Chem. 16, 502–506 (1973).PubMedCrossRefGoogle Scholar
  38. 38.
    P. Sims and P. L. Grover, Epoxides of polycyclic aromatic hydrocarbons: Metabolism and carcinogenesis, Adv. Cancer Res. 20, 166–274 (1974).Google Scholar
  39. 39.
    G. Takahaski and K. Yasuhira, Chromatographic analyses of 3-methylcholanthrene metabolism in adult and fetal mice and the occurrence of conjugating enzymes in the fetus, Cancer Res. 35, 613–620 (1975).Google Scholar
  40. 40.
    A. Rane, N-oxidation of a tertiary amine (N,N-dimethylamline) by human fetal liver microsomes, Clin. Pharmacol. Then 15, 32–38 (1974).Google Scholar
  41. 41.
    O. Pelkonen and N. T. Karki, Epoxidation of xenobiotics in the human fetus and placenta: A possible mechanism of drug-induced injuries, Biochem. Pharmacol. 24, 1445–1448 (1975).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1977

Authors and Affiliations

  • Olavi Pelkonen
    • 1
  1. 1.Department of PharmacologyUniversity of OuluOulu 22Finland

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