Francavilla A, Di Leo A, Eagon P K, Polimeno L, Guglielmi F, Fanizza G, Barone M, Starzl T E
Gastroenterology. 1987 Oct;93(4):681-6. doi: 10.1016/0016-5085(87)90428-8.
Spironolactone and potassium canrenoate are diuretics that are used widely for management of cirrhotic ascites. The administration of spironolactone frequently leads to feminization, which has been noted less frequently with the use of potassium canrenoate, a salt of the active metabolite of spironolactone. The use of these two drugs has been associated with decreases in serum testosterone levels and spironolactone with a reduction in androgen receptor (AR) activity. This decrease in AR has been cited as the cause of the antiandrogen effect of these drugs. We therefore assessed the effect of both drugs on levels of androgen and estrogen receptors (ER) in the liver, a tissue that is responsive to sex steroids. Three groups of male rats (n = 12 rats each) were studied. Group 1 (control) received vehicle only; group 2 received spironolactone (5 mg/day); group 3 received potassium canrenoate (5 mg/day). After 21 days of treatment, the animals of all groups were killed and liver tissue was assayed for nuclear and cytosolic AR and ER, and for male specific estrogen binder (MEB), an androgen-responsive protein. Both drugs drastically decreased the nuclear AR content, as compared with the control group, but only spironolactone decreased cytosolic AR. When the total hepatic content of AR is considered, a highly significant decrease is observed only in rats treated with spironolactone. This reduction in hepatic AR content suggested loss of androgen responsiveness of liver. We confirmed this by assessing levels of MEB, and found that livers from group 2 animals had no detectable MEB activity, whereas livers from both group 1 and 3 had normal MEB activity. No changes were observed in nuclear ER and cytosolic ER of group 3 as compared with group 1. Nuclear estrogen receptor decreased and cytosolic ER increased in group 2, but with no change in total ER content. These results indicate that (a) only spironolactone appears to act as an antiandrogen in liver, resulting in a decrease in both AR and male specific estrogen binder content, and (b) neither drug results in elevated hepatic ER content, although spironolactone-treated animals show an altered subcellular localization.
螺内酯和坎利酸钾是广泛用于治疗肝硬化腹水的利尿剂。螺内酯的使用常常导致女性化，而使用坎利酸钾（螺内酯活性代谢产物的一种盐）这种情况则较少出现。这两种药物的使用都与血清睾酮水平降低有关，且螺内酯会降低雄激素受体（AR）活性。AR的这种降低被认为是这些药物产生抗雄激素作用的原因。因此，我们评估了这两种药物对肝脏中雄激素和雌激素受体（ER）水平的影响，肝脏是对性类固醇有反应的组织。研究了三组雄性大鼠（每组12只）。第1组（对照组）仅接受赋形剂；第2组接受螺内酯（5毫克/天）；第3组接受坎利酸钾（5毫克/天）。治疗21天后，处死所有组的动物，对肝脏组织进行核内和胞质AR及ER以及雄性特异性雌激素结合蛋白（MEB，一种雄激素反应蛋白）的检测。与对照组相比，两种药物都使核内AR含量大幅降低，但只有螺内酯降低了胞质AR。当考虑肝脏AR的总含量时，仅在接受螺内酯治疗的大鼠中观察到高度显著的降低。肝脏AR含量的这种降低表明肝脏雄激素反应性丧失。我们通过评估MEB水平证实了这一点，发现第2组动物的肝脏没有可检测到的MEB活性，而第1组和第3组动物的肝脏具有正常的MEB活性。与第1组相比，第3组的核内ER和胞质ER没有变化。第2组核内雌激素受体减少而胞质ER增加，但总ER含量没有变化。这些结果表明：（a）只有螺内酯在肝脏中似乎起到抗雄激素的作用，导致AR和雄性特异性雌激素结合蛋白含量均降低；（b）两种药物都不会导致肝脏ER含量升高，尽管接受螺内酯治疗的动物显示出亚细胞定位改变。
