Regulation of bile acid synthesis via direct effects on the microsomal membrane

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Abstract
Rats treated with ethinylestradiol (5 mg kg-1 day-1 for 5 days) secrete de novo synthesized bile acids at a markedly reduced rate (-57%). Administration of the nonionic detergent Triton WR-1339 to estradiol-treated rats rapidly restored the rate of secretion of de novo synthesized bile acids to control levels. In contrast, when Triton was administered to control rats, the secretion rate of bile acids was unaffected. The reduction in bile acid synthesis displayed by estradiol-treated rats was similar to the 50% decrease in the activity of hepatic microsomal 7.alpha.-hydroxylase. The activity of 7.alpha.-hydroxylase was also restored to control levels by the administration of Triton to estradiol-treated rats. We examined the possibility that estradiol acts directly on the hepatic microsomes. Adding increasing amounts of estradiol to microsomes obtained from control rats resulted in decreasing activities of 7.alpha.-hydroxylase. The inhibition of estradiol of 7.alpha.-hydroxylase obtained in vitro occurred with amounts of estradiol that were found to accumulate in the liver via in vivo treatment. Double-reciprocal analysis showed that at and below 50 .mu.g of estradiol/0.5 mg of protein uncompetitive inhibition was displayed. Additional experiments showed that adding Triton to microsomes obtained from estradiol-treated rats increased the activity of 7.alpha.-hydroxylase to control levels. In contrast, Triton did not increase the activity of 7.alpha.-hydroxylase when it was added to control microsomes. These data show for the first time that the estrogenic steroid estradiol acts directly on the microsomes and inhibits both the activity of 7.alpha.-hydroxylase and the rate of bile acid synthesis. In addition, Triton also acts on the microsomes and reverses the inhibition of both 7.alpha.-hydroxylase and bile acid synthesis. This is the first demonstration of a method to reverse the inhibition of 7.alpha.-hydroxylase and bile acid synthesis caused by estrogenic steroids.