Abstract
Several cytochrome P450 (CYP) enzymes catalyze the C4-hydroxylation of retinoic acid (RA), a potent inducer of cell differentiation and an agent in the treatment of several diseases. Here, we have characterized CYP2C22, a member of the rat CYP2C family with homology to human CYP2C8 and CYP2C9. CYP2C22 was expressed nearly exclusively in hepatocytes, where it was one of the more abundant mRNAs transcripts. In H-4-II-E rat hepatoma cells, CYP2C22 mRNA was upregulated by all-trans (at)-RA, and Am580, a nonmetabolizable analog of at-RA. In comparison, in primary human hepatocytes, at-RA increased CYP2C9 but not CYP2C8 mRNA. Analysis of the CYP2C22 promoter region revealed a RA response element (5'-GGTTCA-(n)5-AGGTCA-3') in the distal flanking region, which bound the nuclear hormone receptors RAR and RXR and which was required for transcriptional activation response of this promoter to RA in CYP2C22-luciferase-transfected RA-treated HepG2 cells. The cDNA-expressed CYP2C22 protein metabolized [3H]at-RA to more polar metabolites. While long-chain polyunsaturated fatty acids competed, 9-cis-RA was a stronger competitor. Our studies demonstrate that CYP2C22 is a high-abundance, retinoid-inducible, hepatic P450 with the potential to metabolize at-RA, providing additional insight into the role of the CYP2C gene family in retinoid homeostasis.
Highlights
Several cytochrome P450 (CYP) enzymes catalyze the C4-hydroxylation of retinoic acid (RA), a potent inducer of cell differentiation and an agent in the treatment of several diseases
CYP2C22 transcript was analyzed by in situ hybridization in sections of liver tissue from rats in three treatment groups: vitamin A–deficient; vitamin A–repleted; and vitamin A–deficient treated for 6 h with a combination of vitamin A and Am580, a stable analog of RA
In situ hybridization revealed that the liver-specific distribution of CYP2C22 mRNA observed in Fig. 1A represents its expression in hepatocytes and that the level of CYP2C22 mRNA increases rapidly in response to retinoid treatment in vivo
Summary
Several cytochrome P450 (CYP) enzymes catalyze the C4-hydroxylation of retinoic acid (RA), a potent inducer of cell differentiation and an agent in the treatment of several diseases. Members of several families of the cytochrome P450 superfamily have been implicated in the metabolism of vitamin A (retinol) and its principal active metabolite, all-trans-retinoic acid (RA) [5, 6], yet the roles these enzymes play in vivo is still not well understood. Retinoic acid plays a fundamental role in embryogenesis, vertebrate development, cell proliferation, and cell differentiation [7,8,9]. Both RA and numerous synthetic analogs are important agents in the treatment of certain cancers and other disorders [9, 10].
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