Xenobiotic-Metabolizing Enzyme Systems and Aging

  • Christopher R. Barnett
  • Costas Ioannides
Part of the Methods in Molecular Medicine book series (MIMM, volume 38)


The human body is continuously exposed to a wide array of structurally diverse chemicals. Such exposure occurs even at the fetal stage as almost all chemicals that are present in the mother’s blood can readily cross the placenta and reach the fetus. Some of these chemicals are ingested voluntarily, for example, medicines and food additives, but the vast majority are taken involuntarily, as environmental contaminants present in the air or in the occupational environment. Undoubtedly, the most important source of such chemicals is the diet, and many dietary constituents have been shown to induce many forms of toxicity including cancer (1). Exposure to chemicals is thus inevitable and unavoidable. The body cannot exploit these chemicals either to generate energy or transform them to building blocks and consequently its response is to rid itself of their presence. This chapter discusses the role of drug-metabolizing enzyme systems in this process and the effects of age. The measurement of drug-metabolizing activities is of increasing importance in the safety evaluation of drugs in humans. This chapter describes the use of alkylphenoxazone derivatives for investigating selected activities of drug-metabolizing enzymes.


Cytochrome P450 Enzyme Grapefruit Juice Cytochrome P450 Family Cytochrome P450 Activity Sodium Hydrogen Carbonate 
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  1. 1.
    Ioannides, C., ed. (1998) Nutrition and Chemical Toxicity. John Wiley & Sons, Chichester.Google Scholar
  2. 2.
    Hinson, J. A., Pumford, N. R., and Nelson, S. D. (1994) The role of metabolic activation in drug toxicity. Drug Metab. Rev. 26, 395–412.PubMedCrossRefGoogle Scholar
  3. 3.
    Vermeulen, N. P. E. (1996) Role of metabolism in chemical toxicity, in Cytochromes P450: Metabolic and Toxicological Aspects (Ioannides, C., ed.), CRC Press, Boca Raton, FL,. 29–53.Google Scholar
  4. 4.
    Pessayre, D., Dolder, A., Arigou, J. Y., Wandscheer, J.-C., Descatoire, V., Degott, C., and Benhamou, J. P. (1979) Effect of fasting on metabolite-mediated hepatotoxicity in the rat. Gastroenterology 77, 264–271.PubMedGoogle Scholar
  5. 5.
    Kawajiri, K., Yonekawa, H., Hara, T., and Tagashira, Y. (1978) Biochemical basis for the resistance of guinea pigs to carcinogenesis by 2-acetylaminofluorene. Biochem. Biophys. Res. Commun. 85, 959–965.PubMedCrossRefGoogle Scholar
  6. 6.
    Maddrey, W. C. (1987) Hepatic effects of acetaminophen. Enhanced toxicity in alcoholics. J. Clin. Gastroenterol. 9, 180–185.PubMedCrossRefGoogle Scholar
  7. 7.
    Guengerich, F. P. (1993) Cytochrome P-450 enzymes. Am. Scientist 81, 440–447.Google Scholar
  8. 8.
    Ioannides, C. and Parke, D. V. (1990) The cytochrome P450 I gene family of microsomal haemoproteins and their role in their metabolic activation of chemicals. Drug Metab. Rev. 22, 1–85.PubMedCrossRefGoogle Scholar
  9. 9.
    Gonzalez, F. J. and Gelboin H. V. (1994) Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metab. Rev. 26, 165–183.PubMedCrossRefGoogle Scholar
  10. 10.
    Meyer, U. A., Skoda, R. C., and Zanger, U. M. (1990) The genetic polymorphism of debrisoquine/sparteine metabolism-molecular mechanisms. Pharmacol. Ther. 46, 297–308.PubMedCrossRefGoogle Scholar
  11. 11.
    Westin, S., Tollet, P., Ström, A., Mode, A., and Gustafsson, J. Å. (1992) The role and mechanism of growth hormone in the regulation of sexually dimorphic P450 enzymes in rat liver. J. Steroid Biochem. Molec. Biol. 43, 1045–1053.PubMedCrossRefGoogle Scholar
  12. 12.
    Ioannides, C., Barnett, C. R., Irizar, A., and Flatt, P. R. (1996) Expression of cytochrome P450 proteins in disease, in Cytochromes P450: Metabolic and Toxicological Aspects (Ioannides, C., ed.), CRC Press, Boca Raton, FL,. 301–327.Google Scholar
  13. 13.
    Ameer, B. and Weintraub, R. A., 1997, Drug interactions with grapefruit juice. Clin. Pharmacol. 33, 103–121.Google Scholar
  14. 14.
    Dragnev, K. H., Nims, R. W., and Lubet, R. A. (1995) The chemopreventive agent diallyl sulfide. A structurally atypical phenobarbital-type inducer. Biochem. Pharmacol. 50, 2099–2104.PubMedCrossRefGoogle Scholar
  15. 15.
    Guengerich, F. P. and Turvy, C. G. (1991) Comparison of levels of several human cytochrome P-450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J. Pharmacol. Exp. Ther. 256, 1189–1191.PubMedGoogle Scholar
  16. 16.
    Schmucker, D. L. (1985) Aging and drug disposition in the elderly: an update. Pharmacol. Rev. 37, 133–148.PubMedGoogle Scholar
  17. 17.
    Durnas, C., Loi, C.-M., and Cusack, B. J. (1990) Hepatic drug metabolism and aging. Clin. Pharmacokinet. 19, 359–389.PubMedCrossRefGoogle Scholar
  18. 18.
    Wynne, H. A., Mutch, E., James, O. F. W., Rawlins, M. D., and Woodhouse, K. W. (1988) The effect of age upon the affinity of microsomal monooxygenase enzymes for substrate in human liver. Age Ageing 17, 401–405.PubMedCrossRefGoogle Scholar
  19. 19.
    Imaoka, S., Fujita, S., and Funae, Y. (1991) Age-dependent expression of cytochromes P-450s in rat liver. Biochim. Biophys. Acta 1097, 187–192.PubMedGoogle Scholar
  20. 20.
    Hunt, C. M., Westerkam, W. R., Stave, G. M., and Wilson, J. A. P. (1992) Hepatic cytochrome P-4503A (CYP3A) activity in the elderly. Mech. Ageing Dev. 64, 189–499.PubMedCrossRefGoogle Scholar
  21. 21.
    Hunt, C. M., Strater, S., and Stave, G. M. (1990) Effect of normal aging on the activity of human hepatic cytochrome P-450IIE1. Biochem. Pharmacol. 40, 1666–1669.PubMedCrossRefGoogle Scholar
  22. 22.
    Sotaniemi, E. A., Rautio, A., Lumme, P., Arvela, P., and Rautio, A. (1996) Age and CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in man. Therapie 51, 363–366.PubMedGoogle Scholar
  23. 23.
    Sotaniemi, E. A., Arranto, A. J., Pelkonen, O., and Pasanen, M. (1997) Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin. Pharmacol. Ther. 61, 331–339.PubMedCrossRefGoogle Scholar
  24. 24.
    Burke, M. D. and Mayer, R. T. (1974) Ethoxyresorufin: Direct fluorometric assay of microsomal O-dealkylation which is preferentially induced by 3-methylcholanthrene. Drug Metab. Disp. 2, 583–588.Google Scholar
  25. 25.
    Rodrigues, A. D. and Prough, R. A. (1991) Induction of cytochromes P450IA1 and P450IA2 and measurement of catalytic activities. Methods Enzymol. 206, 423–431.PubMedCrossRefGoogle Scholar
  26. 26.
    Ioannides, C. and Parke, D. V. (1975) Mechanism of induction of hepatic microsomal drug metabolising enzymes by a series of barbiturates. J. Pharm. Pharmacol. 27, 739–746.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2000

Authors and Affiliations

  • Christopher R. Barnett
    • 1
  • Costas Ioannides
    • 2
  1. 1.School of Biomedical Sciences, University of UlsterCounty LondonderryNorthern Ireland
  2. 2.School of Biological Sciences, University of SurreyGuildford, SurreyUK

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