Davis R A, Kern F
Gastroenterology. 1976 Jun;70(6):1130-5.
Bile acid synthesis calculated from respiratory (14)CO2 derived from the catabolism of [26 or 27-(14)C]cholesterol to bile acids in rats with intact enterohepatic circulations decreased 50% after 5 days of ethinyl estradiol treatment (5 mg per kg per day). Maximal derepressed bile acid synthesis, measured as biliary bile acid excretion after bile acid pool depletion, was also reduced 50% by ethinyl estradiol treatment. Because ethinyl estradiol did not alter biliary cholesterol excretion, bile contained less bile acid relative to cholesterol. Hepatic bile acid concentration was not increased by ethinyl estradiol treatment. Because the inhibitory effect of ethinyl estradiol on bile acid synthesis required 5 days of treatment it is concluded that bile acid synthesis probably was not reduced by negative feedback repression of 7alpha-hydroxylase, the rate-limiting enzyme in bile acid synthesis, which has a half-life of 2 to 3 hr. During the first 14 hr after bile duct cannulation, before bile acid pool depletion, ethinyl estradiol-treated rats excreted less than one-half as much bile acid and the same amount of cholesterol as controls. The bile acid to cholesterol ratio was therefore decreased. Rats treated simultaneously with phenobarbital and ethinyl estradiol excreted significantly more bile acid than rats treated with ethinyl estradiol alone, but biliary cholesterol excretion was not increased. The proportion of biliary bile acid relative to cholesterol was thereby restored to the control value. In contrast, after 14 hr of bile drainage and depletion of the bile acid pool, rats treated with ethinyl estradiol and those treated with phenobarbital-ethinyl estradiol excreted the same amount of bile acid. Thus, when phenobarbital is administered with ethinyl estradiol, it increases the bile acid pool size and biliary bile acid excretion, but it does not increase bile acid synthesis. The increase in pool size and biliary bile acid excretion might be due to the phenobarbital-induced increase in ileal absorption of bile acids.
在具有完整肝肠循环的大鼠中，从[26或27-(14)C]胆固醇分解代谢为胆汁酸所产生的呼吸性(14)CO2计算得出的胆汁酸合成，在乙炔雌二醇（每天每千克5毫克）处理5天后减少了50%。以胆汁酸池耗竭后胆汁中胆汁酸排泄量衡量的最大去抑制胆汁酸合成，也因乙炔雌二醇处理而减少了50%。由于乙炔雌二醇不改变胆汁中胆固醇的排泄，胆汁中相对于胆固醇的胆汁酸含量减少。乙炔雌二醇处理未使肝胆汁酸浓度升高。由于乙炔雌二醇对胆汁酸合成的抑制作用需要5天的处理时间，因此得出结论，胆汁酸合成可能不是通过胆汁酸合成的限速酶7α-羟化酶的负反馈抑制而减少的，该酶的半衰期为2至3小时。在胆管插管后的最初14小时内，在胆汁酸池耗竭之前，经乙炔雌二醇处理的大鼠排泄的胆汁酸不到对照组的一半，而胆固醇排泄量与对照组相同。因此胆汁酸与胆固醇的比率降低。同时用苯巴比妥和乙炔雌二醇处理的大鼠排泄的胆汁酸明显多于仅用乙炔雌二醇处理的大鼠，但胆汁中胆固醇排泄量未增加。胆汁中胆汁酸相对于胆固醇的比例因此恢复到对照值。相反，在胆汁引流14小时且胆汁酸池耗竭后，用乙炔雌二醇处理的大鼠和用苯巴比妥-乙炔雌二醇处理的大鼠排泄的胆汁酸量相同。因此，当苯巴比妥与乙炔雌二醇一起给药时，它会增加胆汁酸池大小和胆汁中胆汁酸排泄，但不会增加胆汁酸合成。胆汁酸池大小和胆汁中胆汁酸排泄的增加可能是由于苯巴比妥诱导的胆汁酸在回肠吸收增加所致。
