Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters.
Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters.
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乙炔雌二醇胆汁淤积涉及肝窦转运蛋白表达的改变。
DOI：
10.1152/ajpgi.1996.271.6.g1043
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Sutherland,E
中科院分区：
文献类型：
--
作者：
Simon,FR;Fortune,J;Iwahashi,M;Gartung,C;Wolkoff,A;Sutherland,E
乙炔雌二醇引起胆汁淤积的机制仍有争议。炔雌醇给药降低了基础胆汁流量，半衰期（t1/2）为12.5 +/- 0.6 h。与此相反，最初的牛磺胆酸盐的摄取没有显着减少，直到3天的59%的控制和13和10%的控制在5和7天，分别。t1/2为4.3 ± 0.1天。这些生理变化与Na（+）-K（+）-腺苷三磷酸酶（Na（+）-K（+）-ATPase）、Na（+）依赖性牛磺胆酸转运体、有机阴离子转运体和膜脂流动性的蛋白质质量和稳态mRNA的测量相关。炔雌醇显著降低Na（+）-K（+）-ATPase活性和膜流动性。然而，Na（+）-K（+）-ATP酶α亚基和β亚基质量均未被炔雌醇给药改变。相反，Na（+）依赖的牛磺胆酸转运蛋白的蛋白质含量在第5天显著降低至对照组的21%（P < 0.001）。Na（+）依赖性牛磺胆酸转运蛋白在窦膜组分中被鉴定为分子大小估计为51和56 kDa的双峰。虽然这两个带减少与炔雌醇治疗，56 kDa的带下降得更快，并在更大程度上比51 kDa的带。双联体的估计t1/2为4.8 ± 0.6天，与Na（+）依赖性牛磺胆酸盐摄取相似。有机阴离子转运蛋白质质量也随着炔雌醇给药时间的延长而降低，在第5天降至对照组的21%（P < 0.01）。炔雌醇也迅速降低稳态mRNA水平的Na（+）依赖性和有机阴离子转运的约50%和15%的控制，分别在5天。这些研究表明，早期普遍异常的窦膜脂质流动性，Na（+）-K（+）-ATP酶活性，和胆汁酸转运蛋白含量。
The mechanisms involved in ethinyl estradiol-induced cholestasis are controversial. Basal bile flow was reduced by ethinyl estradiol administration, with a half time (t1/2) of 12.5 +/- 0.6 h. In contrast, initial taurocholate uptake was not significantly reduced until 3 days to 59% of control and to 13 and 10% of control at 5 and 7 days, respectively. The t1/2 was 4.3 +/- 0.1 days. These physiological changes were correlated with measurement of protein mass and steady-state mRNA for Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase), Na(+)-dependent taurocholate transporter, organic anion transporters, and membrane lipid fluidity. Ethinyl estradiol significantly decreased Na(+)-K(+)-ATPase activity and membrane fluidity. However, neither Na(+)-K(+)-ATPase alpha-subunit nor beta-subunit mass was altered by ethinyl estradiol administration. In contrast, protein content of the Na(+)-dependent taurocholate transporter was significantly reduced to 21% of control (P < 0.001) at 5 days. The Na(+)-dependent taurocholate transporter was identified in sinusoidal membrane fractions as a doublet with a molecular size estimated to be 51 and 56 kDa. Although both bands were reduced with ethinyl estradiol treatment, the 56-kDa band was decreased more rapidly and to a greater extent than the 51-kDa band. The estimated t1/2 of 4.8 +/- 0.6 days for the doublet was similar to that for Na(+)-dependent taurocholate uptake. The organic anion transporter protein mass was similarly reduced with time of ethinyl estradiol administration to 21% of control (P < 0.01) at 5 days. Ethinyl estradiol also rapidly decreased the steady-state mRNA levels of Na(+)-dependent and organic anion transporters to approximately 50% and 15% of control at 5 days, respectively. These studies indicate early generalized abnormalities of the sinusoidal membrane lipid fluidity, Na(+)-K(+)-ATPase activity, and bile acid transport protein content.