Kirkpatrick R B, Killenberg P G
J Lipid Res. 1980 Sep;21(7):895-901.
Administration of large doses of estrogens has been shown to result in decreased conjugation and increased sulfation of bile acids as well as cholestasis. There have been no previous studies on the effects of low doses of estrogens on these parameters of bile acid metabolism. Therefore, rats were given ethinylestradiol, 0.06 to 600 micrograms/kg/day subcutaneously for up to 21 days and the in vitro activity of the hepatic conjugation and sulfation enzymes was measured. Conjugating enzyme activity was unchanged at doses below 600 micrograms/kg/day. In contrast, hepatic sulfation of conjugated bile acids increased significantly after 21 days treatment with 0.6 micrograms/kg/day. The magnitude of the increase was both time- and dose-dependent. Increased sulfotransferase activity was noted only in the liver and was specific for conjugated bile acids; there was no change in the rate of sulfation of the unconjugated bile acids or in renal sulfotransferase activity. Increased hepatic bile acid sulfotransferase activity occurred in the presence of normal bile flow and bile acid secretion. These data indicate that treatment with doses of ethinylestradiol comparable to those present in oral contraceptives may lead to readily detectable time- and dose-dependent changes in bile acid sulfation without producing cholestasis. The data also suggest that there may be significant differences in the enzymatic sulfation of conjugated and unconjugated bile acids in the liver.
已表明给予大剂量雌激素会导致胆汁酸结合减少、硫酸化增加以及胆汁淤积。此前尚无关于低剂量雌激素对这些胆汁酸代谢参数影响的研究。因此，给大鼠皮下注射乙炔雌二醇，剂量为0.06至600微克/千克/天，持续21天，并测定肝脏结合酶和硫酸化酶的体外活性。在剂量低于600微克/千克/天时，结合酶活性未发生变化。相比之下，用0.6微克/千克/天处理21天后，结合型胆汁酸的肝脏硫酸化显著增加。增加的幅度呈时间和剂量依赖性。仅在肝脏中观察到硫酸转移酶活性增加，且对结合型胆汁酸具有特异性；未结合胆汁酸的硫酸化速率或肾脏硫酸转移酶活性没有变化。在胆汁流动和胆汁酸分泌正常的情况下，肝脏胆汁酸硫酸转移酶活性增加。这些数据表明，给予与口服避孕药中相当剂量的乙炔雌二醇治疗可能会导致胆汁酸硫酸化出现易于检测到的时间和剂量依赖性变化，而不会产生胆汁淤积。数据还表明，肝脏中结合型和未结合型胆汁酸的酶促硫酸化可能存在显著差异。
