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

Medical Research Laboratories, Veterans Administration Medical Center [J. J. L.], and Department of Urologic Surgery [S. A. L., J. K. K., J. J. L.], University of Minnesota Medical School, Minneapolis, Minnesota 55455

Estrogen 2- and 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_m for estrone was 17.0 µM, and V_max was 0.5 pmol per mg protein per min for ESH in renal microsomes derived from castrated hamsters. Different steroidal estrogen substrates exhibited decreasing catechol formation with hamster kidney microsomal preparations in the following order: estrone > d-equilenin > 17ß-estradiol > equilin > ethynyl estradiol > estriol. Except for ß-dienestrol, the stilbene estrogens revealed levels of catechol formation that were similar to 17ß-estradiol. These findings provide a rationale for the weak carcinogenic activity of ethynyl estradiol, estriol, and ß-dienestrol, since they were poor substrates 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 corresponding rat tissue, and catechol estrogen formation was found to be 2.5- to 19-fold higher in the hamster kidney compared to the rat, using various steroidal and stilbene estrogen substrates. Moreover, the finding that a 3.5- to nearly 6-fold decrease, compared to untreated levels, in catechol formation in kidneys but not in livers of -naphthoflavone-exposed hamsters, depending 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.

¹ This investigation was supported by Grant CA 22008 from the National Cancer Institute, NIH, Department of Health and Human Services; Grant 1K07 ES00094 from the National Institute of Environmental Health Sciences, NIH, Department of Health and Human Services; and the General Medical Research Fund of the Veterans Administration. Presented in part at the 65th Annual Meeting of the Endocrine Society, San Antonio, TX, June 8 to 10, 1983 (12).

² To whom requests for reprints should be addressed, at Medical Research Laboratories, Bldg. 49, Veterans Administration Medical Center, 54th Street and 48th Avenue South, Minneapolis, MN 55417.

Received 5/ 7/84. Accepted 9/27/84.

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