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Gene Review

CYP3A  -  cytochrome P450, family 3, subfamily A

Homo sapiens

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Disease relevance of CYP3A


Psychiatry related information on CYP3A

  • Attention should be given to immune toxicity associated with CYP3A4 autoantibodies and cases of alcohol abuse that are accompanied by exposure to drugs and substances that are CYP3A substrates [6].
  • CONCLUSIONS: Individual differences in CYP3A expression do not explain all the interindividual variability in gefitinib exposure [7].

High impact information on CYP3A


Chemical compound and disease context of CYP3A


Biological context of CYP3A


Anatomical context of CYP3A

  • For differentiation of CYP3A4 and -3A7 levels, dehydroepiandrosterone metabolite patterns for expressed CYP3A forms were characterized and used for simultaneous quantitation of protein levels within liver microsome samples [16].
  • Valpromide (0.5-2.0 mM) did not increase histone acetylation or P-gp expression in rat livers, but induced CYP3A expression.Conclusions:Valproic acid increased P-gp expression and function in human tumour cell lines and in rat liver [17].
  • The increased formation of secondary and tertiary metabolites in rat microsomes with high expression of CYP3A1/2 compared with uninduced rats confirmed the role of CYP3A in taxane metabolism [18].
  • In conclusion, the present study suggests that it is possible to predict quantitatively the CYP3A enzyme induction from hepatocyte data [19].
  • In comparison with the gut mucosa, in hepatocytes the spatial sequence of CYP3A and P-glycoprotein is reversed, resulting in different effects when the activity of one or both are changed [20].

Associations of CYP3A with chemical compounds

  • Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5 [21].
  • Thus studies were undertaken to determine the effect of tariquidar, a potent P-glycoprotein inhibitor that does not affect CYP3A activity, on the ERBT and on the CYP3A-mediated metabolism of midazolam, a non-P-glycoprotein substrate [22].
  • Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy [23].
  • METHODS: In study 1 all 15 healthy volunteers received single oral doses of midazolam (7.5 mg), as a CYP3A probe, and gefitinib (500 mg), separated by an appropriate washout period [7].
  • Moreover, by using selective cytochrome P-450 inhibitors and recombinant human CYP3A4 fractions, KNI-272 was determined to be metabolized mainly by the CYP3A isoform [24].

Regulatory relationships of CYP3A

  • CONCLUSIONS: Urinary excretion of 6 beta-hydroxycortisol may be useful as a screening tool in early-phase development to assess the potential for an investigational drug to induce CYP3A [25].

Other interactions of CYP3A

  • The gene CYP3 encoding P450pcn1 (nifedipine oxidase) is tightly linked to the gene COL1A2 encoding collagen type 1 alpha on 7q21-q22.1 [26].
  • For example, species-specific gene duplications and gene conversion events in the CYP2 and CYP3 families have produced different isoforms in rats and humans since the species division over 80 million years ago [27].
  • We suggest that, under conditions when CYP3A5 content represents a significant fraction of the total hepatic CYP3A pool, the contribution of CYP3A5 to the clearance of some drugs may be an important source of interindividual variability [28].
  • 5. Induction of the CYP3 gene family by the glucocorticoid dexamethasone appears to involve the glucocorticoid receptor, but this receptor is not apparently required for induction by metapyrone and a complete molecular understanding of the induction processes is lacking at present [29].
  • 1. A structural model of CYP3A4 is reported on the basis of a novel amino acid sequence alignment between the CYP3 family and CYP102, a bacterial P450 of known crystal structure [30].

Analytical, diagnostic and therapeutic context of CYP3A

  • The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients [15].
  • The effects of valproic acid on CYP3A were assessed by Northern blot analysis and CYP3A activity assays.Key results:Valproic acid (0.5-2.0 mM) induced P-gp expression and function up to 4-fold in vitro [17].
  • These results indicate that, although induction of CYP3A and 2B in cryopreserved SHs is inferior to that in subcultured ones, SHs can maintain the expression and activities of P450s after long-term cryopreservation [31].
  • The increase of 6beta-TH activity (CYP3A-linked), one of the most representative isoforms in humans, was sustained in liver and kidney by means of Western immunoblotting, using rabbit polyclonal antibodies anti CYP3A1/2 [32].
  • Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus pharmacokinetic profile of Chinese renal transplant recipients [33].


  1. Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice. Stedman, C., Robertson, G., Coulter, S., Liddle, C. J. Biol. Chem. (2004) [Pubmed]
  2. Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease. Dowling, T.C., Briglia, A.E., Fink, J.C., Hanes, D.S., Light, P.D., Stackiewicz, L., Karyekar, C.S., Eddington, N.D., Weir, M.R., Henrich, W.L. Clin. Pharmacol. Ther. (2003) [Pubmed]
  3. Association between nonalcoholic hepatic steatosis and hepatic cytochrome P-450 3A activity. Kolwankar, D., Vuppalanchi, R., Ethell, B., Jones, D.R., Wrighton, S.A., Hall, S.D., Chalasani, N. Clin. Gastroenterol. Hepatol. (2007) [Pubmed]
  4. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Chalasani, N., Gorski, J.C., Patel, N.H., Hall, S.D., Galinsky, R.E. Hepatology (2001) [Pubmed]
  5. Hepatotoxicity of the herbal medicine germander: metabolic activation of its furano diterpenoids by cytochrome P450 3A Depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in rat hepatocytes. Lekehal, M., Pessayre, D., Lereau, J.M., Moulis, C., Fouraste, I., Fau, D. Hepatology (1996) [Pubmed]
  6. Autoantibodies against cytochromes P-4502E1 and P-4503A in alcoholics. Lytton, S.D., Helander, A., Zhang-Gouillon, Z.Q., Stokkeland, K., Bordone, R., Aricò, S., Albano, E., French, S.W., Ingelman-Sundberg, M. Mol. Pharmacol. (1999) [Pubmed]
  7. Exploring the relationship between expression of cytochrome P450 enzymes and gefitinib pharmacokinetics. Swaisland, H.C., Cantarini, M.V., Fuhr, R., Holt, A. Clinical pharmacokinetics. (2006) [Pubmed]
  8. CYP3A genetics in drug metabolism. Eichelbaum, M., Burk, O. Nat. Med. (2001) [Pubmed]
  9. In vitro and in vivo drug interactions involving human CYP3A. Thummel, K.E., Wilkinson, G.R. Annu. Rev. Pharmacol. Toxicol. (1998) [Pubmed]
  10. Aflatoxin B1-adduct formation in rat and human small bowel enterocytes. Kolars, J.C., Benedict, P., Schmiedlin-Ren, P., Watkins, P.B. Gastroenterology (1994) [Pubmed]
  11. No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Dilger, K., Denk, A., Heeg, M.H., Beuers, U. Hepatology (2005) [Pubmed]
  12. Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol. Ushiama, H., Echizen, H., Nachi, S., Ohnishi, A. Clin. Pharmacol. Ther. (2002) [Pubmed]
  13. Disposition and miotic effects of oral alfentanil: a potential noninvasive probe for first-pass cytochrome P4503A activity. Kharasch, E.D., Hoffer, C., Walker, A., Sheffels, P. Clin. Pharmacol. Ther. (2003) [Pubmed]
  14. Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. De Berardinis, V., Moulis, C., Maurice, M., Beaune, P., Pessayre, D., Pompon, D., Loeper, J. Mol. Pharmacol. (2000) [Pubmed]
  15. The influence of CYP3A gene polymorphisms on cyclosporine dose requirement in renal allograft recipients. Eng, H.S., Mohamed, Z., Calne, R., Lang, C.C., Mohd, M.A., Seet, W.T., Tan, S.Y. Kidney Int. (2006) [Pubmed]
  16. Developmental expression of the major human hepatic CYP3A enzymes. Stevens, J.C., Hines, R.N., Gu, C., Koukouritaki, S.B., Manro, J.R., Tandler, P.J., Zaya, M.J. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  17. The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver. Eyal, S., Lamb, J.G., Smith-Yockman, M., Yagen, B., Fibach, E., Altschuler, Y., White, H.S., Bialer, M. Br. J. Pharmacol. (2006) [Pubmed]
  18. Metabolism of new-generation taxanes in human, pig, minipig and rat liver microsomes. Gut, I., Ojima, I., Vaclavikova, R., Simek, P., Horsky, S., Linhart, I., Soucek, P., Kondrova, E., Kuznetsova, L.V., Chen, J. Xenobiotica (2006) [Pubmed]
  19. The quantitative prediction of in vivo enzyme-induction caused by drug exposure from in vitro information on human hepatocytes. Kato, M., Chiba, K., Horikawa, M., Sugiyama, Y. Drug Metab. Pharmacokinet. (2005) [Pubmed]
  20. Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Christians, U., Schmitz, V., Haschke, M. Expert opinion on drug metabolism & toxicology. (2005) [Pubmed]
  21. Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Quintieri, L., Geroni, C., Fantin, M., Battaglia, R., Rosato, A., Speed, W., Zanovello, P., Floreani, M. Clin. Cancer Res. (2005) [Pubmed]
  22. The erythromycin breath test reflects P-glycoprotein function independently of cytochrome P450 3A activity. Kurnik, D., Wood, A.J., Wilkinson, G.R. Clin. Pharmacol. Ther. (2006) [Pubmed]
  23. Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women. Unadkat, J.D., Wara, D.W., Hughes, M.D., Mathias, A.A., Holland, D.T., Paul, M.E., Connor, J., Huang, S., Nguyen, B.Y., Watts, D.H., Mofenson, L.M., Smith, E., Deutsch, P., Kaiser, K.A., Tuomala, R.E. Antimicrob. Agents Chemother. (2007) [Pubmed]
  24. Metabolic characterization of a tripeptide human immunodeficiency virus type 1 protease inhibitor, KNI-272, in rat liver microsomes. Kiriyama, A., Nishiura, T., Yamaji, H., Takada, K. Antimicrob. Agents Chemother. (1999) [Pubmed]
  25. Urinary excretion of 6 beta-hydroxycortisol as an in vivo marker for CYP3A induction: applications and recommendations. Kovacs, S.J., Martin, D.E., Everitt, D.E., Patterson, S.D., Jorkasky, D.K. Clin. Pharmacol. Ther. (1998) [Pubmed]
  26. The gene CYP3 encoding P450pcn1 (nifedipine oxidase) is tightly linked to the gene COL1A2 encoding collagen type 1 alpha on 7q21-q22.1. Brooks, B.A., McBride, O.W., Dolphin, C.T., Farrall, M., Scambler, P.J., Gonzalez, F.J., Idle, J.R. Am. J. Hum. Genet. (1988) [Pubmed]
  27. Sex-dependent metabolism of xenobiotics. Mugford, C.A., Kedderis, G.L. Drug Metab. Rev. (1998) [Pubmed]
  28. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Huang, W., Lin, Y.S., McConn, D.J., Calamia, J.C., Totah, R.A., Isoherranen, N., Glodowski, M., Thummel, K.E. Drug Metab. Dispos. (2004) [Pubmed]
  29. Transcriptional activation of cytochrome P450 genes by different classes of chemical inducers. Dogra, S.C., Whitelaw, M.L., May, B.K. Clin. Exp. Pharmacol. Physiol. (1998) [Pubmed]
  30. Molecular modelling of CYP3A4 from an alignment with CYP102: identification of key interactions between putative active site residues and CYP3A-specific chemicals. Lewis, D.F., Eddershaw, P.J., Goldfarb, P.S., Tarbit, M.H. Xenobiotica (1996) [Pubmed]
  31. Cytochrome p450 expression of cultured rat small hepatocytes after long-term cryopreservation. Ooe, H., Kon, J., Miyamoto, S., Ozone, Y., Ninomiya, S., Mitaka, T. Drug Metab. Dispos. (2006) [Pubmed]
  32. Induction and suppression of murine CYP-mediated biotransformation by dithianon: organ- and sex-related differences. Pozzetti, L., Paolini, M., Barillari, J., Cantelli-Forti, G. Cancer Lett. (1999) [Pubmed]
  33. Influence of different allelic variants of the CYP3A and ABCB1 genes on the tacrolimus pharmacokinetic profile of Chinese renal transplant recipients. Cheung, C.Y., Op den Buijsch, R.A., Wong, K.M., Chan, H.W., Chau, K.F., Li, C.S., Leung, K.T., Kwan, T.H., de Vrie, J.E., Wijnen, P.A., van Dieijen-Visser, M.P., Bekers, O. Pharmacogenomics (2006) [Pubmed]
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