Skip to main content
Log in

The human drug metabolizing cytochromes P450

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

The superfamily of heme-thiolate proteins known as the cytochromes P450 is responsible for the oxidative metabolism of the majority of drugs. Thus, the phenotypes of individuals with respect to their levels of catalytically active cytochromes P450 determines to a large part the substantial interindividual variation observed in the metabolic clearance of drugs. Over the past 10 years 15 different human cytochromes P450 involved in drug metabolism have been isolated and characterized to varying degrees. This brief review discusses the characterization of these cytochromes P450 and how this knowledge has been used by the pharmaceutical industry to aid in the development of new drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. D. R. Nelson, T. Kanataki, D. J. Waxman, F. P. Guengerich, R. W. Estrabrook, R. Feyereisen, F. J. Gonzalez, M. J. Coon, I. C. Gunsalus, O. Gotoh, K. Okuda, and D. W. Nebert. The P450 Superfamily: Update on new sequences, gene mapping, accession numbers, early trival names of enzymes, and nomenclature.DNA Cell Biol. 12:1–51 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. S. A. Wrighton and J. C. Stevens. The human cytochromes P450 involved in drug metabolism.Crit. Rev. Toxicol. 22:1–21 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. F. P. Guengerich. Human cytochromes P450. In P. R. Ortiz de Montellano (ed.),Cytochromes P450; Structure, Mechanism, and Biochemistry, Plenum Press, New York, 1995, pp. 473–535.

    Google Scholar 

  4. G. T. Tucker. Clinical implications of genetic polymorphism in drug metabolism.J. Pharm. Pharmacol. 46:417–424 (1994).

    CAS  PubMed  Google Scholar 

  5. A. M. Batt, G. Siest, J. Magdalou, and M. M. Galteau. Enzyme induction by drug and toxins.Clin. Chim. Acta 209:109–121 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. M. Murray. P450 Enzymes; inhibition mechanisms, genetic regulation and effects of liver disease.Clin. Pharmacokin. 23:132–146 (1992).

    Article  CAS  Google Scholar 

  7. S. A. Wrighton, M. VandenBranden, J. C. Stevens, L. A. Shipley, B. J. Ring, A. E. Rettie, and J. R. Cashman.In vitro methods for assessing human hepatic drug metabolism: Their use in drug development.Drug Metab. Rev. 25:453–484 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. S. A. Wrighton, B. J. Ring, and M. VandenBranden. The use ofin vitro metabolism techniques in the planning and interpretation of drug safety studies.Toxicol. Pathol. 23:199–208 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. D. J. Birkett, P. I. Mackenzie, M. E. Veronese, and J. O. Miners.In vitro approaches can predict human drug metabolism.Trends in Pharmacol. Sci. 14:292–294 (1993).

    Article  CAS  Google Scholar 

  10. M. V. Relling, J. S. Lin, G. D. Ayers, and W. E. Evans. Racial and gender differences inN-acetyltransferase, xanthine oxidase, and CYP1A2 activities.Clin. Pharmacol. Ther. 52:643–658 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. P. Fernandez-Saluero, S. M. G. Hoffman, S. Cholerton, H. Mohrenweiser, H. Raunio, A. Rautio, O. Pelkonen, J. Huang, W. E. Evans, J. R. Idle, and F. J. Gonzalez. A genetic polymorphism in coumarin 7-hydroxylation: Sequence of the human CYP2A genes and identification of variant CYP2A6 alleles.Am. J. Hum. Genet. 57:651–660 (1995).

    Google Scholar 

  12. T. Shimada, H. Yamazaki, M. Mimura, Y. Inui, and F. P. Guengerich. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians.J. Pharmacol. Exp. Ther. 270:414–423 (1994).

    CAS  PubMed  Google Scholar 

  13. A. Rahman, K. R. Korzekwa, J. Grogan, F. J. Gonzalez, and J. W. Harris. Selective biotransformation of taxol to 6-alpha-hydroxy taxol by human cytochrome P450 2C8.Cancer Res. 54:5543–5546 (1994).

    CAS  PubMed  Google Scholar 

  14. S. A. Wrighton, J. C. Stevens, G. W. Becker, and M. VandenBranden. Isolation and characterization of human liver cytochrome P450 2C19: Correlation between 2C19 and (S)-mephenytoin 4′-hydroxylation.Arch. Biochem. Biophys. 306:240–245 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. S. M. F. de Morais, G. R. Wilkinson, J. Blaisdell, K. Nakamura, U. A. Meyer, and J. A. Goldstein. The major genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in humans.J. Biol. Chem. 269:15419–15422 (1994).

    PubMed  Google Scholar 

  16. K. Iwahashi, Y. Matsuo, H. Suwaki, K. Nakamura, and Y. Ichikawa. CYP2E1 and ALDH2 genotypes and alcohol dependence in Japanese.Alco. Clin. Exp. Res. 19:564–566 (1995).

    Article  CAS  Google Scholar 

  17. B. J. Ring, C. J. Parli, M. C. George, and S. A. Wrighton.In vitro metabolism of zatosetron: Interspecies comparison and role of CYP3A.Drug Metab. Dispos. 22:352–357 (1994).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wrighton, S.A., VandenBranden, M. & Ring, B.J. The human drug metabolizing cytochromes P450. Journal of Pharmacokinetics and Biopharmaceutics 24, 461–473 (1996). https://doi.org/10.1007/BF02353474

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02353474

Key words

Navigation