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CYP2A6  -  cytochrome P450, family 2, subfamily A,...

Homo sapiens

Synonyms: 1,4-cineole 2-exo-monooxygenase, CPA6, CYP2A, CYP2A3, CYPIIA6, ...
 
 
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Disease relevance of CYP2A6

  • The CYP2A3 and CYP2A6 cDNAs were cloned into baculovirus, and recombinant viruses were used to produce active enzymes in Spodoptera frugiperta (SF9) cells [1].
  • Taking these results into account, CYP2A6 is an enzyme enhancing lung cancer risk [2].
  • The prenatal expression of the CYP2A proteins in the olfactory mucosa suggests potential risks of developmental toxicity from maternally derived xenobiotics, since both CYP2A6 and CYP2A13 are known to be efficient in the metabolic activation of tobacco-specific nitrosamines and other respiratory toxicants [3].
  • The human xenobiotic-metabolizing enzyme cytochrome P450, CYP2A6, catalyzes the bioactivation of a number of carcinogens and drugs and is overexpressed in cases of liver diseases, such as cirrhosis, viral hepatitis, and parasitic infestation, and in certain tumor cells [4].
  • RESULTS: Seven out of 366 patients with liver diseases were anti-CYP2A6 positive [5].
 

Psychiatry related information on CYP2A6

 

High impact information on CYP2A6

 

Chemical compound and disease context of CYP2A6

 

Biological context of CYP2A6

 

Anatomical context of CYP2A6

 

Associations of CYP2A6 with chemical compounds

 

Physical interactions of CYP2A6

  • Chromatin immunoprecipitation assay revealed that PXR and PGC-1alpha bind to CYP2A6 chromatin [27].
  • Mapping of the hnRNP A1 binding site within CYP2A6 3'-UTR reveals that the smallest portion of RNA supporting significant binding consists of 111 central nucleotides of the 3'-UTR [4].
 

Regulatory relationships of CYP2A6

  • CYP2A6/2A7 mRNA was expressed in 61% and CYP2E1 mRNA in 96% of the patients, but in the latter a lower degree of inter-individual variation was observed [22].
  • In this study, we generated a peptide-specific antibody against human CYP2A13 and demonstrated by immunoblot analysis that this antibody does not cross-react with heterologously expressed human CYP2A6 and mouse CYP2A5 proteins, both sharing a high degree of amino acid sequence similarity with CYP2A13 [28].
  • Microsomes containing human cytochrome P450 2A6 (h2A6) coexpressed with human OR (hOR) via a baculovirus expression system displayed coumarin hydroxylase activity with apparent Km and Vmax values of 0.41 microM and 4.05 nmol/min/nmol P450, respectively [29].
  • With the exception of 8-methoxypsoralen, preincubation of human liver microsomes and NADPH with the aforementioned inhibitors did not increase their ability to inhibit CYP2A6 [30].
  • In this work, a new disubstituted indigoid generation system was developed with a tryptophanase-deficient Escherichia coli strain as a host to express the human cytochrome P450 2A6 mutant L240C/N297Q, which catalyzes the oxidation of indole to isatin and indoxyl, which in turn react to generate indigoids [31].
 

Other interactions of CYP2A6

  • A variant CYP2A6 allele that differed from the corresponding CYP2A6 and CYP2A7 cDNAs previously sequenced was found and was designated CYP2A6v2 [18].
  • Furthermore, growth of cultured CYP2A6- and CYP2B6-expressing B-lymphoblastoid cells, but not of CYP-negative control cells, was inhibited by cyclophosphamide and ifosphamide as a consequence of prodrug activation to cytotoxic metabolites [25].
  • Whereas CYP2C8 and CYP2C9 have the characteristics of low Km oxazaphosphorine 4-hydroxylases, CYP2A6, -2B6, and -3A4 are high Km forms [25].
  • When single-dose disulfiram is used as an in vivo probe for P450, inhibition of drug metabolism suggests involvement of CYP2E1 but not CYP2A6 [26].
  • There was a > 10-fold inter-individual variation in expression of the various P450s including CYP3A4 (57-fold), CYP2B6 (56-fold) and CYP2A6 (120-fold) [32].
 

Analytical, diagnostic and therapeutic context of CYP2A6

References

  1. Baculovirus-mediated expression and characterization of rat CYP2A3 and human CYP2a6: role in metabolic activation of nasal toxicants. Liu, C., Zhuo, X., Gonzalez, F.J., Ding, X. Mol. Pharmacol. (1996) [Pubmed]
  2. Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: application of genetically engineered Salmonella expressing human CYP. Kamataki, T., Fujita, K., Nakayama, K., Yamazaki, Y., Miyamoto, M., Ariyoshi, N. Drug Metab. Rev. (2002) [Pubmed]
  3. Immunoblot analysis and immunohistochemical characterization of CYP2A expression in human olfactory mucosa. Chen, Y., Liu, Y.Q., Su, T., Ren, X., Shi, L., Liu, D., Gu, J., Zhang, Q.Y., Ding, X. Biochem. Pharmacol. (2003) [Pubmed]
  4. Interaction of heterogeneous nuclear ribonucleoprotein A1 with cytochrome P450 2A6 mRNA: implications for post-transcriptional regulation of the CYP2A6 gene. Christian, K., Lang, M., Maurel, P., Raffalli-Mathieu, F. Mol. Pharmacol. (2004) [Pubmed]
  5. Cytochrome P450 2A6: a new hepatic autoantigen in patients with chronic hepatitis C virus infection. Dalekos, G.N., Obermayer-Straub, P., Bartels, M., Maeda, T., Kayser, A., Braun, S., Loges, S., Schmidt, E., Gershwin, M.E., Manns, M.P. J. Hepatol. (2003) [Pubmed]
  6. Inhibition of cytochrome P450 2A6 increases nicotine's oral bioavailability and decreases smoking. Sellers, E.M., Kaplan, H.L., Tyndale, R.F. Clin. Pharmacol. Ther. (2000) [Pubmed]
  7. Decreasing smoking behaviour and risk through CYP2A6 inhibition. Sellers, E.M., Tyndale, R.F., Fernandes, L.C. Drug Discov. Today (2003) [Pubmed]
  8. CYP2A6 polymorphisms are associated with nicotine dependence and influence withdrawal symptoms in smoking cessation. Kubota, T., Nakajima-Taniguchi, C., Fukuda, T., Funamoto, M., Maeda, M., Tange, E., Ueki, R., Kawashima, K., Hara, H., Fujio, Y., Azuma, J. Pharmacogenomics J. (2006) [Pubmed]
  9. Metabolism and disposition kinetics of nicotine. Hukkanen, J., Jacob, P., Benowitz, N.L. Pharmacol. Rev. (2005) [Pubmed]
  10. Molecular mimicry of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T cell recognition. Kammer, A.R., van der Burg, S.H., Grabscheid, B., Hunziker, I.P., Kwappenberg, K.M., Reichen, J., Melief, C.J., Cerny, A. J. Exp. Med. (1999) [Pubmed]
  11. Genetic variation of CYP2A6, smoking, and risk of cancer. London, S.J., Idle, J.R., Daly, A.K., Coetzee, G.A. Lancet (1999) [Pubmed]
  12. 2'-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: formation of a lung carcinogen precursor. Hecht, S.S., Hochalter, J.B., Villalta, P.W., Murphy, S.E. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  13. Cytochromes P450 2A6, 2E1, and 3A and production of protein-aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver diseases. Niemelä, O., Parkkila, S., Juvonen, R.O., Viitala, K., Gelboin, H.V., Pasanen, M. J. Hepatol. (2000) [Pubmed]
  14. CYP2A13-catalysed coumarin metabolism: comparison with CYP2A5 and CYP2A6. von Weymarn, L.B., Murphy, S.E. Xenobiotica (2003) [Pubmed]
  15. Quantitative structure-activity relationship analysis of inhibitors of the nicotine metabolizing CYP2A6 enzyme. Rahnasto, M., Raunio, H., Poso, A., Wittekindt, C., Juvonen, R.O. J. Med. Chem. (2005) [Pubmed]
  16. CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk. Nowell, S., Sweeney, C., Hammons, G., Kadlubar, F.F., Lang, N.P. Cancer Epidemiol. Biomarkers Prev. (2002) [Pubmed]
  17. Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Tyndale, R.F., Sellers, E.M. Therapeutic drug monitoring. (2002) [Pubmed]
  18. A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Fernandez-Salguero, P., Hoffman, S.M., Cholerton, S., Mohrenweiser, H., Raunio, H., Rautio, A., Pelkonen, O., Huang, J.D., Evans, W.E., Idle, J.R. Am. J. Hum. Genet. (1995) [Pubmed]
  19. Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Su, T., Bao, Z., Zhang, Q.Y., Smith, T.J., Hong, J.Y., Ding, X. Cancer Res. (2000) [Pubmed]
  20. Human CYP2A6 activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): mutational specificity in the gpt gene of AS52 cells. Tiano, H.F., Wang, R.L., Hosokawa, M., Crespi, C., Tindall, K.R., Langenbach, R. Carcinogenesis (1994) [Pubmed]
  21. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. Oscarson, M., McLellan, R.A., Gullstén, H., Yue, Q.Y., Lang, M.A., Bernal, M.L., Sinues, B., Hirvonen, A., Raunio, H., Pelkonen, O., Ingelman-Sundberg, M. FEBS Lett. (1999) [Pubmed]
  22. CYP2A6/2A7 and CYP2E1 expression in human oesophageal mucosa: regional and inter-individual variation in expression and relevance to nitrosamine metabolism. Godoy, W., Albano, R.M., Moraes, E.G., Pinho, P.R., Nunes, R.A., Saito, E.H., Higa, C., Filho, I.M., Kruel, C.D., Schirmer, C.C., Gurski, R., Lang, M.A., Pinto, L.F. Carcinogenesis (2002) [Pubmed]
  23. Expression and alternative splicing of the cytochrome P-450 CYP2A7. Ding, S., Lake, B.G., Friedberg, T., Wolf, C.R. Biochem. J. (1995) [Pubmed]
  24. Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract. He, X.Y., Tang, L., Wang, S.L., Cai, Q.S., Wang, J.S., Hong, J.Y. Int. J. Cancer (2006) [Pubmed]
  25. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Chang, T.K., Weber, G.F., Crespi, C.L., Waxman, D.J. Cancer Res. (1993) [Pubmed]
  26. Single-dose disulfiram does not inhibit CYP2A6 activity. Kharasch, E.D., Hankins, D.C., Baxter, P.J., Thummel, K.E. Clin. Pharmacol. Ther. (1998) [Pubmed]
  27. Induction of Human CYP2A6 Is Mediated by the Pregnane X Receptor with Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator 1{alpha}. Itoh, M., Nakajima, M., Higashi, E., Yoshida, R., Nagata, K., Yamazoe, Y., Yokoi, T. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  28. CYP2A13 in Human Respiratory Tissues and Lung Cancers: An Immunohistochemical Study with A New Peptide-Specific Antibody. Zhu, L.R., Thomas, P.E., Lu, G., Reuhl, K.R., Yang, G.Y., Wang, L.D., Wang, S.L., Yang, C.S., He, X.Y., Hong, J.Y. Drug Metab. Dispos. (2006) [Pubmed]
  29. Competitive interactions between cytochromes P450 2A6 and 2E1 for NADPH-cytochrome P450 oxidoreductase in the microsomal membranes produced by a baculovirus expression system. Tan, Y., Patten, C.J., Smith, T., Yang, C.S. Arch. Biochem. Biophys. (1997) [Pubmed]
  30. Inhibition of coumarin 7-hydroxylase activity in human liver microsomes. Draper, A.J., Madan, A., Parkinson, A. Arch. Biochem. Biophys. (1997) [Pubmed]
  31. Biosynthesis of new indigoid inhibitors of protein kinases using recombinant cytochrome P450 2A6. Wu, Z.L., Aryal, P., Lozach, O., Meijer, L., Guengerich, F.P. Chem. Biodivers. (2005) [Pubmed]
  32. In vitro metabolism of aflatoxin B1 by normal and tumorous liver tissue from Thailand. Kirby, G.M., Wolf, C.R., Neal, G.E., Judah, D.J., Henderson, C.J., Srivatanakul, P., Wild, C.P. Carcinogenesis (1993) [Pubmed]
  33. Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method. Chen, G.F., Tang, Y.M., Green, B., Lin, D.X., Guengerich, F.P., Daly, A.K., Caporaso, N.E., Kadlubar, F.F. Pharmacogenetics (1999) [Pubmed]
  34. Measurement of cytochrome P450 2A6 and 2E1 gene expression in primary human bronchial epithelial cells. Crawford, E.L., Weaver, D.A., DeMuth, J.P., Jackson, C.M., Khuder, S.A., Frampton, M.W., Utell, M.J., Thilly, W.G., Willey, J.C. Carcinogenesis (1998) [Pubmed]
  35. Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. Oscarson, M., McLellan, R.A., Gullstén, H., Agúndez, J.A., Benítez, J., Rautio, A., Raunio, H., Pelkonen, O., Ingelman-Sundberg, M. FEBS Lett. (1999) [Pubmed]
  36. High variability of nitrosamine metabolism among individuals: role of cytochromes P450 2A6 and 2E1 in the dealkylation of N-nitrosodimethylamine and N-nitrosodiethylamine in mice and humans. Camus, A.M., Geneste, O., Honkakoski, P., Béréziat, J.C., Henderson, C.J., Wolf, C.R., Bartsch, H., Lang, M.A. Mol. Carcinog. (1993) [Pubmed]
  37. Comparison of cytochrome P450 2A6 polymorphism frequencies in Caucasians and African-Americans using a new one-step PCR-RFLP genotyping method. Paschke, T., Riefler, M., Schuler-Metz, A., Wolz, L., Scherer, G., McBride, C.M., Bepler, G. Toxicology (2001) [Pubmed]
 
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