April 2010

[JLR] Retinoids and CYPs

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CYP2C22 mRNA transcripts barely are detectable in the liver of vitamin A-deficient rats (left) but, upon treatment with vitamin A, increased dramatically (right).

Cytochrome P450s (CYPs) are known for their important roles in metabolizing both xenobiotic drugs and endogenous compounds. Several members of this family are believed to metabolize vitamin A and its derivative, retinoic acid (RA). In this study, the authors characterized CYP2C22 from rat, a member of the CYP2C family that shares homology to human CYP2C8 and CYP2C9. They found that CYP2C22 was expressed almost exclusively in hepatocytes, where it was quite abundant. CYP2C22 mRNA was upregulated by all-trans-RA and the nonmetabolizable at-RA analog am580, whereas in human hepatocytes, at-RA increased the expression of CYP2C9 but not CYP2C8. Analysis of the CYP2C22-promoter region revealed an RA-response element in the distal-flanking region; this region could bind to the nuclear hormone receptors RAR and RXR and was required for transcriptional activation in response to RA treatment. In metabolic assays, 9-cis-RA was revealed to be an especially strong competitor for at-RA, though 9-cis-RA was not converted to other metabolites by the enzyme, suggesting it functions as an inhibitor but apparently not as a competitive substrate. Together, this work provides additional insight into the role of the CYP2C family in retinoid metabolism.

Liver-specific Cytochrome P450 CYP2C22 Is a Direct Target of Retinoic Acid and a Retinoic Acid-metabolizing Enzyme in Rat Liver

Linxi Qian, Reza Zolfaghari and A. Catharine Ross

J. Lipid Res., published online Feb. 10, 2010

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