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Gene Review

CYP2A  -  cytochrome P450, family 2, subfamily A

Homo sapiens

Synonyms: CYP1, CYP2, P450C2, P450C2A, P450PB
 
 
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Disease relevance of CYP2A

 

High impact information on CYP2A

  • Mouse lines having one or another of the Cyp1 genes disrupted have shown paradoxical effects; in the test tube or in cell culture these enzymes show metabolic activation of PAHs or arylamines, whereas in the intact animal these enzymes are sometimes more important in the role of detoxification than metabolic potentiation [6].
  • Differences in AHR affinity between inbred mouse strains reflect variations in CYP1 inducibility and clearly have been shown to be associated with differences in risk of toxicity or cancer caused by PAHs and arylamines [6].
  • The human hepatocytes in the murine host liver expressed mRNAs for a variety of human cytochrome P450 (hCYP) subtypes, in a manner that was similar to the donor liver [7].
  • This cis-acting element is highly homologous to the hepatocyte nuclear factor 4 (HNF-4) binding motif and is present in the promoters of more than 20 other CYP2 genes [8].
  • All the reported point mutations and chimeric fragments that significantly affect the substrate specificities of the parental CYP2 enzymes fell within or overlapped some of the six SRSs [9].
 

Chemical compound and disease context of CYP2A

  • CYP1A2 is one of the major CYP1 enzymes that catalyse 2-hydroxylation of estrogen, a hormone that plays a critical role in the etiology of breast cancer [10].
 

Biological context of CYP2A

  • The involvement of CYP2A in the metabolic activation of NNK in the lung was first evidenced by the fact that the mutagenic activation of NNK by mouse lung microsomes was inhibited by 8-methoxypsoralen, coumarin and antibodies to rat CYP2A1 [1].
  • The cluster of genes on human chromosome 19 from the CYP2A, 2B, and 2F subfamilies has been previously described as having a complex organization and many pseudogenes [11].
  • The CYP2A and CYP2B subfamilies are known to lie within 350 kb of each other on chromosome 19 [12].
  • Recently, the organization and structures of the CYP2A gene cluster and several polymorphic alleles of the CYP2A6 gene have been characterized [13].
  • 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 [14].
 

Anatomical context of CYP2A

  • These results suggest that human CYP2A6 and rat CYP2C11 are the major catalysts in the metabolism of (-)-verbenone by liver microsomes and that there are species-related differences in human and rat CYP2A enzymes and sex-related differences in male and female rats in the metabolism of (-)-verbenone [15].
  • In the present study, the regional distribution and cell-specific expression of CYP2A in the rat nasal cavity were examined using an antibody to rabbit CYP2A10/11 [16].
  • While P450s immunochemically related to the rabbit CYP2As have been detected in rat and human nasal mucosa, confirmation of these enzymes as members of the CYP2A subfamily and efforts to characterize their ability to bioactivate toxicants have been limited [16].
  • In sections of the anterior nose, immunoreactive CYP2A was present in ciliated cells of the nasal respiratory epithelium and cuboidal epithelial cells of the nasal transitional epithelium, but was absent in squamous epithelial cells [16].
  • Where epidermal expression has been localized in situ by hybridization or immunocytochemistry, CYP2 transcripts and proteins are most often expressed in differentiated keratinocytes comprising the outer (suprabasal) cell layers of the epidermis and skin appendages [17].
 

Associations of CYP2A with chemical compounds

 

Other interactions of CYP2A

  • Thus, examples of each of the xenobiotic-metabolizing CYP1, CYP2, and CYP3 subfamilies were detected in low levels in human normal breast tissue and tumors [21].
  • CYP2 (CYP510A3, 499 amino acids) were highly similar to each other (87% identical) and they had 32-33% identities to that of Coprinus cinereus P450 (CYP502) and 27-28% identities to those of two Aspergillus P450s (CYP64 family) [22].
  • At least 13 CYP2 genes (CYP2A6, 2A7, 2B6, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 2R1, 2S1, 2U1, and 2W1) are expressed in skin from at least some human individuals, and the majority of these genes are expressed in epidermis or cultured keratinocytes [17].
  • The predicted 504 amino acid sequence displays 38--49% identity with CYP2 family members and the protein was designated CYP2S1. mRNA dot blot analysis demonstrated high expression levels in trachea, lung, stomach, small intestine, and spleen [23].
  • Compared to other divisions of the CYP2 gene family, the CYP2F subfamily is unusual in having few genes per species and in being selectively expressed in lung tissues [24].
 

Analytical, diagnostic and therapeutic context of CYP2A

  • To determine the locations of CYP2F1 with respect to CYP2A and CYP2B, multipoint linkage analysis and pulsed-field gel electrophoresis were performed [12].
  • Immunoblotting analysis of microsomes from VCH-treated rodents revealed elevated levels of CYP2A and CYP2B in mice but not rats [19].
  • Furthermore, an analysis of CYP2A sequence alignment suggests that CYP2A7P2 may be derived from the same ancestral gene that gave rise to CYP2A7P1, which was corrupted by a large insertion at intron 5 [25].
  • Molecular modeling studies based on the recent CYP2C5 crystal structure appear to show close agreement with site-directed mutagenesis experiments and with information on substrate metabolism and selectivity within the CYP2 family [26].
  • Quantitative RT-PCR analysis of the transcripts of Le. cyp1 and Le. cyp2 genes in the course of fruiting-body development of L. edodes showed that the primordium seems to contain larger amounts of these transcripts [22].

References

  1. Mechanisms of chemopreventive effects of 8-methoxypsoralen against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung adenomas. Miyazaki, M., Yamazaki, H., Takeuchi, H., Saoo, K., Yokohira, M., Masumura, K., Nohmi, T., Funae, Y., Imaida, K., Kamataki, T. Carcinogenesis (2005) [Pubmed]
  2. Linkage relationships of the apolipoprotein C1 gene and a cytochrome P450 gene (CYP2A) to myotonic dystrophy. Walsh, K.V., Harley, H.G., Brook, J.D., Rundle, S.A., Sarfarazi, M., Harper, P.S., Shaw, D.J. Hum. Genet. (1990) [Pubmed]
  3. Metabolic activation of carcinogens and expression of various cytochromes P450 in human prostate tissue. Williams, J.A., Martin, F.L., Muir, G.H., Hewer, A., Grover, P.L., Phillips, D.H. Carcinogenesis (2000) [Pubmed]
  4. Does selenium reduce the risk of threatened preterm delivery associated with placental cytochrome P450-1A1 activity? Huel, G., Campagna, D., Girard, F., Moreau, T., Blot, P. Environmental research. (2000) [Pubmed]
  5. Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort. Chaudhary, A., Willett, K.L. Toxicology (2006) [Pubmed]
  6. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. Nebert, D.W., Dalton, T.P., Okey, A.B., Gonzalez, F.J. J. Biol. Chem. (2004) [Pubmed]
  7. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Tateno, C., Yoshizane, Y., Saito, N., Kataoka, M., Utoh, R., Yamasaki, C., Tachibana, A., Soeno, Y., Asahina, K., Hino, H., Asahara, T., Yokoi, T., Furukawa, T., Yoshizato, K. Am. J. Pathol. (2004) [Pubmed]
  8. A transcriptional regulatory element common to a large family of hepatic cytochrome P450 genes is a functional binding site of the orphan receptor HNF-4. Chen, D., Lepar, G., Kemper, B. J. Biol. Chem. (1994) [Pubmed]
  9. Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. Gotoh, O. J. Biol. Chem. (1992) [Pubmed]
  10. Population-based case-control study of AhR (aryl hydrocarbon receptor) and CYP1A2 polymorphisms and breast cancer risk. Long, J.R., Egan, K.M., Dunning, L., Shu, X.O., Cai, Q., Cai, H., Dai, Q., Holtzman, J., Gao, Y.T., Zheng, W. Pharmacogenet. Genomics (2006) [Pubmed]
  11. Organization, structure and evolution of the CYP2 gene cluster on human chromosome 19. Hoffman, S.M., Nelson, D.R., Keeney, D.S. Pharmacogenetics (2001) [Pubmed]
  12. Localization of CYP2F1 by multipoint linkage analysis and pulsed-field gel electrophoresis. Bale, A.E., Mitchell, A.L., Gonzalez, F.J., McBride, O.W. Genomics (1991) [Pubmed]
  13. Polymorphisms of CYP2A6 and its practical consequences. Raunio, H., Rautio, A., Gullstén, H., Pelkonen, O. British journal of clinical pharmacology. (2001) [Pubmed]
  14. Sex-dependent metabolism of xenobiotics. Mugford, C.A., Kedderis, G.L. Drug Metab. Rev. (1998) [Pubmed]
  15. Roles of human CYP2A6 and 2B6 and rat CYP2C11 and 2B1 in the 10-hydroxylation of (-)-verbenone by liver microsomes. Miyazawa, M., Sugie, A., Shimada, T. Drug Metab. Dispos. (2003) [Pubmed]
  16. Nasal cytochrome P450 2A: identification, regional localization, and metabolic activity toward hexamethylphosphoramide, a known nasal carcinogen. Thornton-Manning, J.R., Nikula, K.J., Hotchkiss, J.A., Avila, K.J., Rohrbacher, K.D., Ding, X., Dahl, A.R. Toxicol. Appl. Pharmacol. (1997) [Pubmed]
  17. Epidermal CYP2 family cytochromes P450. Du, L., Hoffman, S.M., Keeney, D.S. Toxicol. Appl. Pharmacol. (2004) [Pubmed]
  18. 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]
  19. Role of induction of specific hepatic cytochrome P450 isoforms in epoxidation of 4-vinylcyclohexene. Fontaine, S.M., Hoyer, P.B., Halpert, J.R., Sipes, I.G. Drug Metab. Dispos. (2001) [Pubmed]
  20. Induction of CYP1A and cyp2-mediated arachidonic acid epoxygenation and suppression of 20-hydroxyeicosatetraenoic acid by imidazole derivatives including the aromatase inhibitor vorozole. Diani-Moore, S., Papachristou, F., Labitzke, E., Rifkind, A.B. Drug Metab. Dispos. (2006) [Pubmed]
  21. Expression of cytochromes P450 in human breast tissue and tumors. Huang, Z., Fasco, M.J., Figge, H.L., Keyomarsi, K., Kaminsky, L.S. Drug Metab. Dispos. (1996) [Pubmed]
  22. Cloning and expression of cytochrome P450 genes, belonging to a new P450 family, of the basidiomycete Lentinula edodes. Akiyama, R., Sato, Y., Kajiwara, S., Shishido, K. Biosci. Biotechnol. Biochem. (2002) [Pubmed]
  23. Identification and tissue distribution of the novel human cytochrome P450 2S1 (CYP2S1). Rylander, T., Neve, E.P., Ingelman-Sundberg, M., Oscarson, M. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  24. Identification and cross-species comparisons of CYP2F subfamily genes in mammals. Chen, N., Whitehead, S.E., Caillat, A.W., Gavit, K., Isphording, D.R., Kovacevic, D., McCreary, M.B., Hoffman, S.M. Mutat. Res. (2002) [Pubmed]
  25. Identification of a new human CYP2A gene fragment with close linkage to CYP2GP1. Sheng, J., Hua, Z., Guo, J., Caggana, M., Ding, X. Drug Metab. Dispos. (2001) [Pubmed]
  26. Essential requirements for substrate binding affinity and selectivity toward human CYP2 family enzymes. Lewis, D.F. Arch. Biochem. Biophys. (2003) [Pubmed]
 
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