Estrogen 2- and 4-Hydroxylase Activity, Catechol Estrogen Formation, and Implications for Estrogen Carcinogenesis in the Hamster Kidney1

Estrogen 2and 4-hydroxylase (ESH), a microsomal enzyme which mediates the formation of catechol estrogens, has been studied in the kidneys of castrated male Syrian hamsters, a species uniquely susceptible to induction of renal carcinomas by both steroidal and stilbene estrogens. The apparent K„, for estrone was 17.0 MM,and V,™«, was 0.5 pmol per mg protein per min for ESH in renal microsomes derived from castrated ham sters. Different steroidal estrogen substrates exhibited decreas ing catechol formation with hamster kidney microsomal prepa rations in the following order: estrone > d-equilenin > 17/3estradiol > equilin > ethynyl estradiol > estriol. Except for ßdienestrol, the stilbene estrogens revealed levels of catechol formation that were similar to 170-estradiol. These findings pro vide a rationale for the weak carcinogenic activity of ethynyl estradiol, estriol, and 0-dienestrol, since they were poor sub strates for hamster renal ESH and for the relatively potent carcinogenic activity of the distal metabolite of diethylstilbestrol, indenestrol B/A, which exhibited substantial levels of o-hydroxylation when used as a substrate. Interestingly, ESH activity was significantly greater in the hamster kidney compared to corre sponding rat tissue, and catechol estrogen formation was found to be 2.5to 19-fold higher in the hamster kidney compared to the rat, using various steroidal and stilbene estrogen substrates. Moreover, the finding that a 3.5to nearly 6-fold decrease, compared to untreated levels, in catechol formation in kidneys but not in livers of a-naphthoflavone-exposed hamsters, depend ing on the steroidal or stilbene estrogen substrate used, is consistent with the belief that the catechol estrogen pathway is pertinent to events leading to estrogen-induced renal tumorigenesis in the hamster.