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

Abstract

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 CYP 1A1 induced by 3-methylcholanthrene (3-MC) catalyzed the conversion of retinal 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-MC—pretreated rats as the enzyme source. In 3-MC—treated rats, retinal and retinol, but not retinoic acid, inhibited benzo(a)pyrene metabolism. The 50% inhibitory concentration (IC 50) of retinal was about 11.5 μmol/L and the inhibition was competitive, with a K i value of 5.8 μmol/L. Retinol is a more potent inhibitor than retinal. The IC 50 was about 5 μmol/L and the inhibition was mixed, with a K i value of 19.2 μmol/L and a K i ′ value of 4.2 μmol/L. Almost the same results were obtained for the reaction of 7-ethoxyresorufin deethylation. In contrast, the metabolic activity of both benzo(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 with retinoid metabolism should be taken into account when studying the anticarcinogenic action of retinoids.