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Cyp1a2  -  cytochrome P450, family 1, subfamily a,...

Mus musculus

Synonyms: CP12, CYPIA2, Cyp1a-2, Cyp1a1, Cytochrome P450 1A2, ...
 
 
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Disease relevance of Cyp1a2

  • Fetuses from Cyp1a2(-/-) dams exhibited a approximately 6-fold increased sensitivity to cleft palate, hydronephrosis, and lethality [1].
  • In a cultured hepatoma CYP1A1 metabolism-deficient mutant line that does not express Cyp1a2, we have previously shown that constitutive transcriptional up-regulation of other [Ah] gene battery members occurs; these results are consistent with the elevation of a putative endogenous ligand (EL) for the Ah receptor that is a substrate for CYP1A1 [2].
  • Endpoints such as thymic involution, Cyp1a2 induction, hepatomegaly, and hydropic degeneration remain unchanged in this model [3].
  • The incidence of lymphoma was higher in Cyp1a2-null females than wild-type females treated with low dose (600 nmol) PhIP whereas no significant differences were observed in other treatment groups of mice [4].
  • Higher incidences of hepatocellular adenoma were observed in Cyp1a2-null female and male mice as compared with wild-type mice [4].
 

High impact information on Cyp1a2

  • In contrast, Cyp1a2 gene expression was positive in liver irrespective of the presence or absence of the AhR gene, or B[a]P treatment, although its inducibility was lost in the AhR(-/-) mouse [5].
  • Moreover, mRNA levels of Cyp1a1, the other gene in the same subfamily, appear unaffected by loss of the Cyp1a2 gene [6].
  • CYP1A2 substrates include aflatoxin B1, acetaminophen, and a variety of environmental arylamines [6].
  • To define better the developmental and metabolic functions of this enzyme, we developed a CYP1A2-deficient mouse line by homologous recombination in embryonic stem cells [6].
  • Expression of CYP1A2 is induced after exposure to certain aromatic hydrocarbons (i.e., 2,3,7,8-tetrachlorodibenzo-p-dioxin) [7].
 

Chemical compound and disease context of Cyp1a2

 

Biological context of Cyp1a2

 

Anatomical context of Cyp1a2

  • Dioxin levels were highest in adipose tissue, mammary gland, and circulating blood of Cyp1a2(-/-) mothers, compared with that in the Cyp1(+/+) mothers, who showed highest dioxin levels in liver [1].
  • Cell-density-dependent expression of Cyp1a2 gene in monolayer-cultured adult mouse hepatocytes [16].
  • Cyp1a2 protects against reactive oxygen production in mouse liver microsomes [17].
  • In Cyp1a2(-/-) mice, H(2)O(2) production was the same for induced and noninduced microsomes, with levels significantly higher than those in wild-type mice [17].
  • Histological examination confirmed a decrease in hepatocellular damage in TCDD-treated Cyp1a2(-/-) mice; in particular, there was no bile duct damage or proliferation that in the Cyp1a2(+/+) mice might be caused by uroporphyrin [18].
 

Associations of Cyp1a2 with chemical compounds

  • More dioxin reached the embryos from Cyp1a2(-/-) dams, compared with that from Cyp1(+/+) dams [1].
  • Acenaphthylene was the most potent inducer of MROD, a Cyp1a2-dependent activity, and was utilized as a prototypical inducer for this group of tricyclic hydrocarbons [13].
  • However, phenobarbital induction was unexpectedly higher, while beta-naphthoflavone induction of the reporter was much lower than that of the endogenous Cyp1a2 gene [14].
  • Immature (21 days old) AhR, Cyp1a2, or Cyp1b1 knockout (-/-) mice were treated intraperitoneally with estradiol (E2, 20 ng/mouse per day, for 14 consecutive days) and/or TCDD (200 ng/mouse per day, on days 7, 9, 11, and 13) [19].
  • The induction of P450 cytochromes Cyp1a1 and Cyp1a2 in the liver of male mice differing in sensitivity to the carcinogenic effect of o-aminoazotoluene (OAT) has been studied [20].
 

Regulatory relationships of Cyp1a2

 

Other interactions of Cyp1a2

  • In the DB[a,l]P-treated mice, levels of DNA adducts were significantly lower in Cyp1a2(-/-) and Cyp1b1(-/-) mice by 57 and 46%, respectively, as compared to wild-type (WT) mice (C57BL/6 background) [23].
  • Examining mRNA, protein, and enzyme activity, we demonstrate that the absence of CYP1A1 has no effect on the hepatic constitutive expression of Cyp1a2 or Nqo1 [2].
  • To test the combined roles of CYP1A2 and CYP2E1 in an intact animal model, a double-null mouse line lacking functional expression of CYP1A2 and CYP2E1 was produced by cross-breeding Cyp1a2-/- mice with Cyp2e1-/- mice [24].
  • Lower basal Cyp1a2 mRNA levels and lower expression of Cyp1a2 and Cyp3a11 mRNAs after APAP dosing were also observed in females compared with males [25].
  • Regulation of CYP1A2 by histone deacetylase inhibitors in mouse hepatocytes [22].
 

Analytical, diagnostic and therapeutic context of Cyp1a2

References

  1. For dioxin-induced birth defects, mouse or human CYP1A2 in maternal liver protects whereas mouse CYP1A1 and CYP1B1 are inconsequential. Dragin, N., Dalton, T.P., Miller, M.L., Shertzer, H.G., Nebert, D.W. J. Biol. Chem. (2006) [Pubmed]
  2. Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery. Dalton, T.P., Dieter, M.Z., Matlib, R.S., Childs, N.L., Shertzer, H.G., Genter, M.B., Nebert, D.W. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  3. Aspects of dioxin toxicity are mediated by interleukin 1-like cytokines. Pande, K., Moran, S.M., Bradfield, C.A. Mol. Pharmacol. (2005) [Pubmed]
  4. Carcinogenesis of the food mutagen PhIP in mice is independent of CYP1A2. Kimura, S., Kawabe, M., Yu, A., Morishima, H., Fernandez-Salguero, P., Hammons, G.J., Ward, J.M., Kadlubar, F.F., Gonzalez, F.J. Carcinogenesis (2003) [Pubmed]
  5. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Shimizu, Y., Nakatsuru, Y., Ichinose, M., Takahashi, Y., Kume, H., Mimura, J., Fujii-Kuriyama, Y., Ishikawa, T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Liang, H.C., Li, H., McKinnon, R.A., Duffy, J.J., Potter, S.S., Puga, A., Nebert, D.W. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  7. Neonatal lethality associated with respiratory distress in mice lacking cytochrome P450 1A2. Pineau, T., Fernandez-Salguero, P., Lee, S.S., McPhail, T., Ward, J.M., Gonzalez, F.J. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  8. Role of CYP2A5 and 2G1 in acetaminophen metabolism and toxicity in the olfactory mucosa of the Cyp1a2(-/-) mouse. Genter, M.B., Liang, H.C., Gu, J., Ding, X., Negishi, M., McKinnon, R.A., Nebert, D.W. Biochem. Pharmacol. (1998) [Pubmed]
  9. Decrease in 4-aminobiphenyl-induced methemoglobinemia in Cyp1a2(-/-) knockout mice. Shertzer, H.G., Dalton, T.P., Talaska, G., Nebert, D.W. Toxicol. Appl. Pharmacol. (2002) [Pubmed]
  10. Role of CYP1A2 in the toxicity of long-term phenacetin feeding in mice. Peters, J.M., Morishima, H., Ward, J.M., Coakley, C.J., Kimura, S., Gonzalez, F.J. Toxicol. Sci. (1999) [Pubmed]
  11. A hepatocarcinogenic tryptophan-pyrolyzate component, Trp-P-1, decreases serum total testosterone level and induces hepatic Cyp1a2 in male mice. Degawa, M., Hanaki, K., Sekimoto, M. Cancer Sci. (2006) [Pubmed]
  12. Metabolism and hepatic toxicity of flutamide in cytochrome P450 1A2 knockout SV129 mice. Matsuzaki, Y., Nagai, D., Ichimura, E., Goda, R., Tomura, A., Doi, M., Nishikawa, K. J. Gastroenterol. (2006) [Pubmed]
  13. Aryl hydrocarbon (Ah) receptor-independent induction of Cyp1a2 gene expression by acenaphthylene and related compounds in B6C3F1 mice. Chaloupka, K., Santostefano, M., Goldfarb, I.S., Liu, G., Myers, M.J., Tsyrolv, I.B., Gelboin, H.V., Krishnan, V., Safe, S. Carcinogenesis (1994) [Pubmed]
  14. A Cyp1a2-luciferase transgenic CD-1 mouse model: responses to aryl hydrocarbons similar to the humanized AhR mice. Zhang, W., Moorthy, B., Chen, M., Muthiah, K., Coffee, R., Purchio, A.F., West, D.B. Toxicol. Sci. (2004) [Pubmed]
  15. Sensitivity of CYP1A1 mRNA inducibility by dioxin is the same in Cyp1a2(+/+) wild-type and Cyp1a2(-/-) null mutant mice. Liang, H.C., McKinnon, R.A., Nebert, D.W. Biochem. Pharmacol. (1997) [Pubmed]
  16. Cell-density-dependent expression of Cyp1a2 gene in monolayer-cultured adult mouse hepatocytes. Nemoto, N., Sakurai, J. Jpn. J. Cancer Res. (1993) [Pubmed]
  17. Cyp1a2 protects against reactive oxygen production in mouse liver microsomes. Shertzer, H.G., Clay, C.D., Genter, M.B., Schneider, S.N., Nebert, D.W., Dalton, T.P. Free Radic. Biol. Med. (2004) [Pubmed]
  18. Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Smith, A.G., Clothier, B., Carthew, P., Childs, N.L., Sinclair, P.R., Nebert, D.W., Dalton, T.P. Toxicol. Appl. Pharmacol. (2001) [Pubmed]
  19. Role of the aryl hydrocarbon receptor and Cyp1b1 in the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Takemoto, K., Nakajima, M., Fujiki, Y., Katoh, M., Gonzalez, F.J., Yokoi, T. Arch. Toxicol. (2004) [Pubmed]
  20. Expression of CYP1A in liver of A/Sn and CC57BR mice differing in sensitivity to hepatocarcinogenesis induced by o-aminoazotoluene. Timofeeva, O.A., Filipenko, M.L., Rychkova, N.A., Gulyaeva, L.F., Lyakhovich, V.V. Biochemistry Mosc. (2000) [Pubmed]
  21. Use of a novel real-time quantitative reverse transcription-polymerase chain reaction method to study the effects of cytokines on cytochrome P450 mRNA expression in mouse liver. Pan, J., Xiang, Q., Ball, S. Drug Metab. Dispos. (2000) [Pubmed]
  22. Regulation of CYP1A2 by histone deacetylase inhibitors in mouse hepatocytes. Jin, B., Ryu, D.Y. J. Biochem. Mol. Toxicol. (2004) [Pubmed]
  23. Role of cytochrome p4501 family members in the metabolic activation of polycyclic aromatic hydrocarbons in mouse epidermis. Kleiner, H.E., Vulimiri, S.V., Hatten, W.B., Reed, M.J., Nebert, D.W., Jefcoate, C.R., DiGiovanni, J. Chem. Res. Toxicol. (2004) [Pubmed]
  24. Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Zaher, H., Buters, J.T., Ward, J.M., Bruno, M.K., Lucas, A.M., Stern, S.T., Cohen, S.D., Gonzalez, F.J. Toxicol. Appl. Pharmacol. (1998) [Pubmed]
  25. Acetaminophen metabolism does not contribute to gender difference in its hepatotoxicity in mouse. Dai, G., He, L., Chou, N., Wan, Y.J. Toxicol. Sci. (2006) [Pubmed]
  26. In situ hybridization of Cyp1a1, Cyp1a2 and Ah receptor mRNAs expressed in murine ocular tissues. McAvoy, M., Singh, A.K., Shichi, H. Exp. Eye Res. (1996) [Pubmed]
  27. Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice. Sinclair, P.R., Gorman, N., Dalton, T., Walton, H.S., Bement, W.J., Sinclair, J.F., Smith, A.G., Nebert, D.W. Biochem. J. (1998) [Pubmed]
  28. Development of a toxicological gene array and quantitative assessment of this technology. Bartosiewicz, M., Trounstine, M., Barker, D., Johnston, R., Buckpitt, A. Arch. Biochem. Biophys. (2000) [Pubmed]
  29. Intrinsic hepatic phenotype associated with the Cyp1a2 gene as shown by cDNA expression microarray analysis of the knockout mouse. Smith, A.G., Davies, R., Dalton, T.P., Miller, M.L., Judah, D., Riley, J., Gant, T., Nebert, D.W. EHP toxicogenomics : journal of the National Institute of Environmental Health Sciences. (2003) [Pubmed]
 
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