CYP2C7 EXPRESSION IN RAT-LIVER AND HEPATOCYTES - REGULATION BY RETINOIDS

Rats deficient in vitamin A express low levels of P4502C7 mRNA in the liver. Administration of all-trans retinoic acid (at-RA) or growth hor mone (GH) to deficient animals only partially restored the expression whereas the combined treatment returned the P4502C7 mRNA levels to tha t observed in normal rats. That a retinoid is the predominant inducer of P4502C7 at the cellular level is evident from studies performed wit h primary hepatocytes, but it became clear that GH is a prerequisite f or the vitamin A effect in vivo. The at-RA induction of P4502C7 mRNA i n primary rat hepatocytes was inhibited by ketoconazole, an inhibitor of P450 activity, and by cycloheximide, blocking ongoing protein synth esis. In contrast, the at-RA induction of RAR-beta 2 mRNA was not affe cted by any of these compounds. This could indicate previously not rec ognized mechanisms of at-RA action. Interestingly, at-4-oxo-RA, an at- RA metabolite formed by a P450 catalyzed reaction, also induced P4502C 7 mRNA. Induction of P4502C7 mRNA by the retinoic acid receptor (RAR) selective agonist TTNPB indicated that this pathway is preferred over the retinoid X receptor (RXR) pathway. In addition, analysis of RA met abolites in liver cell extracts revealed the formation of several as y et unidentified metabolites. The formation of some of these metabolite s was inhibited by ketoconazole and they could therefore constitute po tential inducers of CYP2C7. We suggest that metabolism of at-RA, possi bly by a P450 enzyme, is an important step in the at-RA induction of P 4502C7. (C) 1997 Elsevier Science Ireland Ltd.