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Gene Review

Cyp4a1  -  cytochrome P450, family 4, subfamily a,...

Rattus norvegicus

Synonyms: CYPIVA10, Cyp4a-1, Cyp4a10, Cyp4a22, Cytochrome P450 4A10, ...
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Disease relevance of Cyp4a10

  • In WBF, as well as in other foci subpopulations and in hepatocellular carcinomas the occurrence of five NAF-inducible enzymes, i.e. of peroxisomal beta-oxidation (acyl-CoA oxidase, bifunctional protein and thiolase), catalase and cytochrome P-452 was studied by immunohistochemical methods [1].
  • Bifonazole, but not clotrimazole, exhibited the characteristics of a peroxisome proliferator including hepatomegaly (increase in liver:body weight ratio), up to a 4-fold induction of lauric acid omega-hydroxylase activity and an 8-fold induction of palmitoyl-CoA oxidation by rat liver peroxisomes [2].

High impact information on Cyp4a10

  • The catalytic site of rat hepatic lauric acid omega-hydroxylase. Protein versus prosthetic heme alkylation in the omega-hydroxylation of acetylenic fatty acids [3].
  • Lauric acid omega-hydroxylase (cytochrome P-450LA omega) was purified from livers of rats that had been given the hypolipidemic drug clofibrate [4].
  • Isolation, complementary DNA sequence, and regulation of rat hepatic lauric acid omega-hydroxylase (cytochrome P-450LA omega). Identification of a new cytochrome P-450 gene family [4].
  • Accompanying the increased expression of CYP4A3 and CYP4A8 mRNA in the prehypertensive rats were corresponding changes in functional CYP4A measured as either arachidonic acid or lauric acid omega-hydroxylase activity (1.4-2.0-fold increases) and CYP4A protein levels [5].
  • In agreement with studies on the cognate RNA, expression of Cyp4a12 protein was male-specific in the liver of control mice and extremely high inducibility of Cyp4a10 protein, with no sex differences, was also demonstrated [6].

Biological context of Cyp4a10

  • The gene coding for the clofibrate-induced cytochrome P-452 has been isolated from a cDNA library and a full-length cDNA clone sequenced [7].
  • Such a sex difference of hepatic LAH activity was not observed in other strains of mice, including BALB/c and C57BL/6 [8].
  • By contrast, the values of IC50 and Ki of testosterone 7alpha-hydroxylase (TS7AH) and lauric acid omega-hydroxylase (LAOH) for BPA were >1000 microM [9].
  • Two overlapping yeast artificial chromosome (YAC) clones were isolated, and the three Cyp4a genes were shown to be present on a single YAC of 220 kb [6].
  • In view of the overlapping patterns of inducibility of the three Cyp4a genes, we investigated whether the three genes were co-localized in the genome [6].

Anatomical context of Cyp4a10

  • Fenofibric acid concomitantly induced LAH activity and peroxisomal PCOA in rat hepatocytes [10].
  • The CYP4A gene family, designated the Cyp4a locus, was mapped to mouse chromosome 4 using a panel of mouse-hamster somatic cell hybrids [11].
  • Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin [1].
  • From the same microsomes, three of the strongly induced P-450 isozymes, i.e., high- and low-spin P-448s and P-452, were purified [12].
  • In addition, immunochemical quantitation of cytochrome P-452 in control, uninduced rat liver microsomes revealed that this particular isoenzyme constituted 22% of the total carbon monoxide-discernible cytochrome P-450 population [13].

Associations of Cyp4a10 with chemical compounds

  • Anti-CYP4A1 antibody inhibited LAH activity, but not lauric acid (omega-1)-hydroxylase activity [8].
  • Furthermore, in male mice, orchiectomy caused a dramatic decrease in hepatic LAH activity and the activity was restored by testosterone treatment to the level of the intact animal [8].
  • No effect of Irgasan DP300 on lauric acid omega-hydroxylase (LAOH) activity was evident in any microsomal preparations [14].
  • Lauric acid omega-hydroxylase (LAOH) was also increased by 1.4-fold by simazine at 200 and 400 mumol/kg [15].
  • However, the activities of other P450-dependent monooxygenases, namely 7-ethoxyresorufin O-deethylase (EROD), 7-benzyloxyresorufin O-debenzylase (BROD), aminopyrine N-demethylase (APND), erythromycin N-demethylase (EMND), lauric acid omega-hydroxylase (LAOH), and testosterone 7alpha-hydroxylase (T7AH) were not affected by 1,1-DCE at any dose [16].

Other interactions of Cyp4a10

  • In addition, a reconstituted enzyme system containing highly purified cytochrome P-452 actively catalyses the above specific oxidation of arachidonic acid, a reaction that is significantly stimulated by the presence of cytochrome b5 [13].
  • The minimal molecular weight of each form was as follows: P-451 I (49,000), P-451 II (52,000), P-450 II (52,000), P-450 III (53,500), P-452 (48,000), P-448 L (56,000), P-448 H (54,000) [17].

Analytical, diagnostic and therapeutic context of Cyp4a10

  • Using a specific ELISA method, we have shown that the cytochrome P-452 isoenzyme is induced up to ten fold by hypolipidaemic challenge, concomitant with a pronounced elevation of the peroxisomal beta-oxidation enzymes, mirrored by an increase in peroxisomal volume as determined morphometrically [18].
  • We have examined the ability of a commercial mixture of polychlorinated biphenyls (Aroclor 1254) to induce hepatic cytochrome P-452-linked enzyme activities in rat and pigeon liver five days after its intraperitoneal injection [19].
  • Our studies have also shown that arachidonic acid serves as an excellent substrate for hypolipidaemic-induced cytochrome P-452, resulting in the formation of several metabolites that have been separated by reverse phase HPLC [13].
  • All of the hypolipidaemic drugs tested significantly induced the hydroxylation of lauric acid and, furthermore, this was accompanied by a concomitant 3-fold induction of a specific isoenzyme of cytochrome P-450 (termed cytochrome P-452) as determined by a single radial immunodiffusion technique [13].
  • After treatment of rats with di(2-ethylhexyl)phthalate (DEHP) a dose-dependent induction of lauric acid omega-hydroxylase activities, levels of cytochrome P450 4A1 and peroxisomal fatty acid beta-oxidation was found [20].


  1. Enhancement of peroxisomal enzymes, cytochrome P-452 and DNA synthesis in putative preneoplastic foci of rat liver treated with the peroxisome proliferator nafenopin. Grasl-Kraupp, B., Huber, W., Just, W., Gibson, G., Schulte-Hermann, R. Carcinogenesis (1993) [Pubmed]
  2. Bifonazole, but not the structurally-related clotrimazole, induces both peroxisome proliferation and members of the cytochrome P4504A sub-family in rat liver. Sabzevari, O., Hatcher, M., Kentish, P., O'Sullivan, M., Gibson, G.G. Toxicology (1996) [Pubmed]
  3. The catalytic site of rat hepatic lauric acid omega-hydroxylase. Protein versus prosthetic heme alkylation in the omega-hydroxylation of acetylenic fatty acids. CaJacob, C.A., Chan, W.K., Shephard, E., Ortiz de Montellano, P.R. J. Biol. Chem. (1988) [Pubmed]
  4. Isolation, complementary DNA sequence, and regulation of rat hepatic lauric acid omega-hydroxylase (cytochrome P-450LA omega). Identification of a new cytochrome P-450 gene family. Hardwick, J.P., Song, B.J., Huberman, E., Gonzalez, F.J. J. Biol. Chem. (1987) [Pubmed]
  5. Developmentally regulated expression of the CYP4A genes in the spontaneously hypertensive rat kidney. Kroetz, D.L., Huse, L.M., Thuresson, A., Grillo, M.P. Mol. Pharmacol. (1997) [Pubmed]
  6. A novel murine P-450 gene, Cyp4a14, is part of a cluster of Cyp4a and Cyp4b, but not of CYP4F, genes in mouse and humans. Heng, Y.M., Kuo, C.S., Jones, P.S., Savory, R., Schulz, R.M., Tomlinson, S.R., Gray, T.J., Bell, D.R. Biochem. J. (1997) [Pubmed]
  7. Differential splicing in the 3' non-coding region of rat cytochrome P-452 (P450 IVA1) mRNA. Earnshaw, D., Dale, J.W., Goldfarb, P.S., Gibson, G.G. FEBS Lett. (1988) [Pubmed]
  8. Sex and strain differences in constitutive expression of fatty acid omega-hydroxylase (CYP4A-related proteins) in mice. Hiratsuka, M., Matsuura, T., Watanabe, E., Sato, M., Suzuki, Y. J. Biochem. (1996) [Pubmed]
  9. Interaction of bisphenol A with rat hepatic cytochrome P450 enzymes. Hanioka, N., Jinno, H., Tanaka-Kagawa, T., Nishimura, T., Ando, M. Chemosphere (2000) [Pubmed]
  10. Fenofibrate: metabolism and species differences for peroxisome proliferation in cultured hepatocytes. Cornu-Chagnon, M.C., Dupont, H., Edgar, A. Fundamental and applied toxicology : official journal of the Society of Toxicology. (1995) [Pubmed]
  11. The rat clofibrate-inducible CYP4A subfamily. II. cDNA sequence of IVA3, mapping of the Cyp4a locus to mouse chromosome 4, and coordinate and tissue-specific regulation of the CYP4A genes. Kimura, S., Hardwick, J.P., Kozak, C.A., Gonzalez, F.J. DNA (1989) [Pubmed]
  12. Inductive effect on hepatic enzymes and toxicity of congeners of PCBs and PCDFs. Yoshimura, H., Yoshihara, S., Koga, N., Nagata, K., Wada, I., Kuroki, J., Hokama, Y. Environ. Health Perspect. (1985) [Pubmed]
  13. Immunochemical study on the contribution of hypolipidaemic-induced cytochrome P-452 to the metabolism of lauric acid and arachidonic acid. Bains, S.K., Gardiner, S.M., Mannweiler, K., Gillett, D., Gibson, G.G. Biochem. Pharmacol. (1985) [Pubmed]
  14. Interaction of 2,4,4'-trichloro-2'-hydroxydiphenyl ether with microsomal cytochrome P450-dependent monooxygenases in rat liver. Hanioka, N., Omae, E., Nishimura, T., Jinno, H., Onodera, S., Yoda, R., Ando, M. Chemosphere (1996) [Pubmed]
  15. Changes in rat liver cytochrome P450 enzymes by atrazine and simazine treatment. Hanioka, N., Jinno, H., Tanaka-Kagawa, T., Nishimura, T., Ando, M. Xenobiotica (1998) [Pubmed]
  16. Changes in cytochrome P450 enzymes by 1,1-dichloroethylene in rat liver and kidney. Hanioka, N., Jinno, H., Nishimura, T., Ando, M. Arch. Toxicol. (1997) [Pubmed]
  17. Purification and characterization of seven distinct forms of liver microsomal cytochrome P-450 from untreated and inducer-treated male Wistar rats. Nagata, K., Buppodom, P., Matsunaga, T., Ishimatsu, M., Yamato, H., Yoshihara, S., Yoshimura, H. J. Biochem. (1985) [Pubmed]
  18. Microsomal cytochrome P-452 induction and peroxisome proliferation by hypolipidaemic agents in rat liver. A mechanistic inter-relationship. Sharma, R., Lake, B.G., Foster, J., Gibson, G.G. Biochem. Pharmacol. (1988) [Pubmed]
  19. Evidence for the induction of cytochrome P-452 in rat liver by Aroclor 1254, a commercial mixture of polychlorinated biphenyls. Borlakoglu, J.T., Edwards-Webb, J.D., Dils, R.R., Wilkins, J.P., Robertson, L.W. FEBS Lett. (1989) [Pubmed]
  20. Microsomal lauric acid hydroxylase activities after treatment of rats with three classical cytochrome P450 inducers and peroxisome proliferating compounds. Dirven, H.A., van den Broek, P.H., Peters, J.G., Noordhoek, J., Jongeneelen, F.J. Biochem. Pharmacol. (1992) [Pubmed]
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