Inhibition by retinoids of benzo(A)pyrene metabolism catalyzed by 3-methylcholanthrene-induced rat cytochrome P-450 1A1

Benzo(a)pyrene, a well-known procarcinogen, is believed to be activated by microsomal cytochrome P-450 1A1 (CYP 1A1). We recently reported that rat CY P 1A1 induced by 3-methylcholanthrene (3-MC) catalyzed the conversion of re tinal to retinoic acid. In this study, we investigated retinoid inhibition of the metabolism of benzo(a)pyrene and 7-ethoxyresorufin. another specific substrate of CYP 1A1, using liver microsomes prepared from control and 3-M C-pretreated rats as the enzyme source. In 3-MC-treated rats, retinal and r etinol, but not retinoic acid, inhibited benzo(a)pyrene metabolism. The 50% inhibitory concentration (IC50) Of retinal was about 11.5 mu mol/L and the inhibition was competitive, with a K-i value of 5.8 mu mol/L. Retinol is a more potent inhibitor than retinal. The IC50 was about 5 mu mol/L and the inhibition was mixed, with a K-i value of 19.2 mu mol/L and a K-i' value of 4.2 mu mol/L. Almost the same results were obtained for the reaction of 7- ethoxyresorufin deethylation. In contrast, the metabolic activity of both b enzo(a)pyrene and 7-ethoxyresorufin was much lower in untreated versus 3-MC -treated rats, and only weak inhibition by the retinoids was observed. The results suggest that retinoids inhibit the activation of benzo(a)pyrene and that the substrate specificity of cytochrome P-450 isozymes associated wit h retinoid metabolism should be taken into account when studying the antica rcinogenic action of retinoids. Copyright (C) 1999 by W.B. Saunders Company .