Detoxification Pathways in the Liver

  • D. M. Grant

Summary

The liver plays an important rôle in protecting the organism from potentially toxic chemical insults through its capacity to convert lipophiles into more water-soluble metabolites which can be efficiently eliminated from the body via the urine. This protective ability of the liver stems from the expression of a wide variety of xenobiotic biotransforming enzymes whose common underlying feature is their ability to catalyse the oxidation, reduction and hydrolysis (Phase I) and/or conjugation (Phase II) of functional groups on drug and chemical molecules. The broad substrate specificity, isoenzyme multiplicity and inducibility of many of these enzyme systems make them particularly well adapted to handling the vast array of different chemical structures in the environment to which we are exposed daily. However, some chemicals may also be converted to more toxic metabolites by certain of these enzymes, implying that variations in the latter may be important predisposing factors for toxicity. Pharmacogenetic defects of xenobiotic biotransformation enzymes, a subclass of inborn errors of metabolism which are manifested only upon drug challenge, introduce marked variation into human populations for the pharmacokinetics and pharmacodynamics of therapeutic and toxic agents, and thus may have important clinical consequences for drug efficacy and toxicity.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Arnaud, M. J. Products of metabolism of caffeine. In: Dews, P. B. (ed.), Caffeine, Springer-Verlag, Berlin, 1984, pp. 3–38CrossRefGoogle Scholar
  2. Blum, M., Grant, D. M., Demierre, A. and Meyer, U. A. N-acetylation pharmacogenetics: a gene deletion causes absence of arylamine N-acetyltransferase in liver of slow acetylator rabbits. Proc. Natl. Acad. Sci. USA 86 (1989) 9554–9557PubMedCrossRefGoogle Scholar
  3. Blum, M., Grant, D. M., McBride, W., Heim, M. and Meyer, U. A. Human arylamine Nacetyltransferase genes: isolation, chromosomal localization, and functional expression. DNA Cell Biol. 9 (1990) 193–203PubMedCrossRefGoogle Scholar
  4. Blum, M., Demierre, A., Grant, D. M., Heim, M. and Meyer, U. A. Molecular mechanism of slow acetylation of drugs and carcinogens in man. Proc. Natl. Acad. Sci. USA (1991) (in press)Google Scholar
  5. Evans, D. A. P. N-acetyltransferase. Pharmacol. Ther. 42 (1989) 157–234PubMedCrossRefGoogle Scholar
  6. Gonzalez, F. J. The molecular biology of cytochrome P450s. Pharmacol. Rev. 40 (1989) 243–288Google Scholar
  7. Grant, D. M., Tang, B. K. and Kalow, W. A simple test for acetylator phenotype using caffeine. Br. J. Clin. Pharmacol. 17 (1984) 459–464PubMedCrossRefGoogle Scholar
  8. Grant, D. M., Lottspeich, F. and Meyer, U. A. Evidence for two closely related isozymes of arylamine N-acetyltransferase in human liver. FEBS Lett. 244 (1989) 203–207PubMedCrossRefGoogle Scholar
  9. Grant, D. M., Moerike, K., Eichelbaum, M. and Meyer, U. A. Acetylation pharmacogenetics: the slow acetylator phenotype is caused by decreased or absent arylamine N-acetyltransferase in human liver. J. Clin. Invest. 85 (1990) 968–972PubMedCrossRefGoogle Scholar
  10. Grant, D. M., Blum, M., Beer, M. and Meyer, U. A. Monomorphic and polymorphic human arylamine N-acetyltransferases: a comparison of liver isoenzymes and expressed products of two cloned genes. Mol. Pharmacol. 39 (1991) 184–191PubMedGoogle Scholar
  11. Jakoby, W. B. Detoxication: conjugation and hydrolysis. In Arias, I. M., Jakoby, W. B., Popper, H., Schacter, D. and Shafritz, D. A. (eds.), The Liver: Biology and Pathobiology, Raven Press, New York, 1988, pp. 375–388Google Scholar
  12. Meyer, U. A. Molecular genetics and the future of pharmacogenetics. Pharmacol. Ther. 46 (1990) 349–355PubMedCrossRefGoogle Scholar
  13. Meyer, U. A., Zanger, U. M., Grant, D. M. and Blum, M. Genetic polymorphisms of drug metabolism. Adv. Drug Res. 19 (1990) 197–241Google Scholar
  14. Miller, E. C. Some current perspectives on chemical carcinogenesis in humans and experimental animals. Cancer Res. 38 (1978) 1479–1496PubMedGoogle Scholar
  15. Nebert, D. W., Nelson, D. R. and Feyereisen, R. Evolution of the cytochrome P450 genes. Xenobiotica 19 (1989) 1149–1160PubMedCrossRefGoogle Scholar
  16. Ohsako, S. and Deguchi, T. Cloning and expression of cDNAs for polymorphic and monomorphic arylamine N-acetyltransferases from human liver. J. Biol. Chem. 265 (1990) 4630–4634PubMedGoogle Scholar
  17. Okey, A. B. Enzyme induction in the cytochrome P450 system. Pharmacol. Ther. 45 (1990) 241–298PubMedCrossRefGoogle Scholar
  18. Spielberg, S. P. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans. Fed. Proc. 43 (1984) 2308–2313PubMedGoogle Scholar
  19. Ziegler, D. M. Detoxication: oxidation and reduction. In Arias, I. M., Jakoby, W. B., Popper, H., Schacter, D. and Shafritz, D. A. (eds.), The Liver: Biology and Pathobiology, Raven Press, New York, 1988, pp. 363–374Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1991

Authors and Affiliations

  • D. M. Grant
    • 1
  1. 1.Division of Clinical Pharmacology and Toxicology, Research InstituteHospital for Sick ChildrenTorontoCanada

Personalised recommendations