Effect of P450 isozyme-selective inhibitors on in-vitro metabolism of retinoic acid by rat hepatic microsomes

Cytochrome P450-mediated 4-hydroxylation of retinoic acid is an important pathway in the termination of its biological action and the activity of certain P450 isozymes has been studied in non-induced male rat hepatic microsomes using isozyme-selective inhibitors. The importance of the activity of the isozyme to retinoic acid metabolism was, 2A6 (diethyl dithiocarbamate as selective inhibitor) > 1A1/1A2 (7,8-benzoflavone)>> 1A1 (ellipticine) > 3A4 (naringenin, ketoconazole) as shown by the respective apparent IC50 values of 0.12, 0.34, 2.7, 9.25 and 13.5 mu M with 2C8-10, 2D6 and 2E1 having little effect on metabolism. It is concluded that although the P450 3A family normally constitutes half the total rat hepatic P450 activity, other hepatic isozymes (1A1, 1A2 and 2A6) are also involved in retinoic acid metabolism. This suggests that the horizons for the design of potential anticancer agents acting through inhibition of retinoic acid metabolism may be widened to include structures which do not resemble the established hetereocyclic base P450 3A4 inhibitors.