CYTOCHROME-P450 METABOLISM OF ESTRADIOL IN HAMSTER LIVER AND KIDNEY

Estradiol induces kidney tumors in Syrian hamsters. The elevated conve rsion of estradiol to 4-hydroxylated metabolites in kidney compared to the predominant 2-hydroxylation in liver and other organs, where tumo rs are not induced by this treatment, has been proposed to be the basi s of estrogen-induced carcinogenesis. In this study, we examined the h epatic and renal enzymes catalyzing the formation of catecholestrogens to understand the differences in estrogen metabolism in these organs. In liver, 2-hydroxylation of estradiol is the major metabolic pathway with 4-hydroxylation a minor by-product and with the formation of bot h catechols responding coordinately to the same inhibitors. Western bl ot analysis and inhibition studies suggest that the major form catalyz ing hepatic estrogen 2-hydroxylation is a member of the CYP3A family, as previously observed with rat liver microsomes, and that 4-hydroxyla tion is a by-product of this metabolism. In the kidney, 4-hydroxylatio n of estradiol appears to be catalyzed by more than one enzyme accordi ng to the Eadie-Hofstee analysis. Both 2- and 4-hydroxylation in the k idney are affected differentially by inhibitors and are induced by bet a-napthoflavone. Western blots of renal microsomes reveal that CYP1A2 is induced whereas CYP1A1 is detectable in kidney, but not induced by this treatment. Finally, a part of the 2-hydroxylation and a small par t of the I-hydroxylation by kidney microsomes may be catalyzed by a me mber of the CYP3A family, since these reactions are partially inhibite d by CYP3A inhibitors such as progesterone and other progestins, altho ugh renal enzyme levels are much lower than those in the liver as reve aled by Western blot. Our data suggest that estrogen 2-hydroxylation i n the hamster kidney is catalyzed by members of the CYP1A and CYP3A fa milies, which also contribute to 4-hydroxylation. The majority of 4-hy droxyestradiol formation in the hamster kidney may be catalyzed by a f orm(s) of the newly discovered CYP1B family that has yet to be charact erized. (C) 1997 Academic Press.