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Effect of Dietary 2(3)-tert-Butyl-4-hydroxyanisole on the Metabolism and Action of Estradiol and Estrone in Female CD-1 Mice¹

Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08855-0789 [B. T. Z., A. H. C.], and Center for Advanced Food Technology, Cook College, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08903 [J. L., R. T. R.]

Administration of 0.75% 2(3)-tert-butyl-4-hydroxyanisole (BHA) in AIN-76A diet to female CD-1 mice for 3 weeks increased liver microsomal glucuronidation of estradiol, estrone, 4-aminophenol, and 4-nitrophenol by 103, 187, 162, and 92%, respectively (at pH 7.4). The overall rate of NADPH-dependent metabolism of estradiol and estrone by liver microsomes of BHA-treated animals as determined by substrate disappearance was increased by 20–40% over that by liver microsomes from control animals. The rate of 2-hydroxylation of estradiol and estrone (the major metabolic pathway) was increased by 24–38%, the rate of formation of 6-hydroxyestradiol plus 6ß-hydroxyestradiol was increased by 90–115%, and the rate of 6ß-hydroxyestrone formation (a minor metabolite formed in liver microsomes from control mice) was increased by approximately 370% over controls. In contrast, BHA administration had little or no effect on the liver microsomal formation of 4- and 16-hydroxylated estradiol and estrone metabolites. Measurable levels of estradiol and estrone were observed in the serum and uterus of ovariectomized CD-1 mice at 30 min after a single i.p. injection of 100 or 300 ng of estradiol or estrone, and these levels were decreased by 30–60% in animals fed a 0.75% BHA diet for 18 days prior to the injection of estrogen. Feeding a 0.75% BHA-supplemented diet to ovariectomized CD-1 mice for 18 days inhibited the uterotropic effect of estradiol or estrone (45 or 75 ng/mouse, i.p. once daily for 3 days) as compared to the response of animals fed the control diet. BHA administration also inhibited estradiol- or estrone-stimulated [³H]thymidine incorporation into uterine DNA. In conclusion, feeding a 0.75% BHA-supplemented diet to female CD-1 mice for 2–3 weeks increased the activities of liver microsomal enzymes that catalyze uridine 5'-diphosphoglucuronic acid-dependent glucuronidation and NADPH-dependent oxidation of estradiol and estrone, enhanced the in vivo metabolism of these estrogens, and inhibited their uterotropic action.

¹ This research was supported by NIH Grants CA 49756 and ESO 05022.

² To whom requests for reprints should be addressed. Phone: (908) 445-4940; Fax: (908) 445-0687.

Received 11/25/96. Accepted 4/10/97.

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