Effect of dietary 2(3)-tert-butyl-4-hydroxyanisole on the metabolism and action of estradiol and estrone in female CD-1 mice.
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 6alpha-hydroxyestradiol plus 6beta-hydroxyestradiol was increased by 90-115%, and the rate of 6beta-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 16alpha-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.
Zhu
B T
BT
Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08855-0789, USA.
Lech
J
J
Rosen
R T
RT
Conney
A H
AH
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002083:Butylated Hydroxyanisole / Q000008:administration & dosage / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D004967:Estrogens / Q000032:analysis / Q000097:blood; D004970:Estrone / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005503:Food Additives / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D013997:Time Factors; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D014599:Uterus / Q000737:chemistry / Q000187:drug effects
D000975:Antioxidants; D004967:Estrogens; D005503:Food Additives; D002083:Butylated Hydroxyanisole; D014535:Uridine Diphosphate Glucuronic Acid; D004970:Estrone; D004958:Estradiol; D009249:NADP