Biliary secretion of glutathione in estradiol 17β-D-glucuronide-induced cholestasis
Biliary secretion of glutathione in estradiol 17β-D-glucuronide-induced cholestasis
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DOI：
10.1124/jpet.103.054544
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
Vore, M
中科院分区：
文献类型：
--
作者：
Mottino, AD;Veggi, LM;Vore, M
雌二醇-17β-D-葡萄糖醛酸 (E2-17G) 静脉注射给大鼠后，会引起胆汁流量的急性但可逆的抑制，部分原因是小管多药耐药相关转运蛋白 2 和胆汁盐输出泵（有助于胆汁流量的转运蛋白）的内吞修复。胆汁盐依赖性胆汁流量（BSIF）减少也参与其中，并在胆汁淤积恢复阶段持续存在。由于谷胱甘肽和 HCO3- 是 BSIF 的主要贡献者，因此我们评估了 E2-17G 诱导的胆汁淤积期间它们的胆汁排泄和总谷胱甘肽的肝脏含量的变化。 E2-17G 使胆汁流量和总谷胱甘肽的胆汁排泄急剧减少约 80%；即使胆汁流量分别部分和完全恢复，谷胱甘肽排泄在 80 分钟和 120 分钟仍受到抑制。肝脏谷胱甘肽含量以及胆汁和肝脏中氧化型谷胱甘肽的比例在任何时候都不受E2-17G的影响。胆汁中的 HCO3- 浓度没有变化，因此分泌与胆汁流量的变化平行。在离体灌注肝脏中，添加E2-17G可降低胆汁流量和谷胱甘肽的胆汁浓度，而添加其非胆汁淤积异构体雌二醇-3-D-葡萄糖醛酸（E2-3G）不会抑制胆汁流量，但显着降低胆汁中谷胱甘肽的浓度。 E2-17G在体内显着降低了谷胱甘肽的胆汁：肝脏浓度比，并且E2-17G和E2-3G在灌注肝脏中显着降低了谷胱甘肽的胆汁：肝脏浓度比。这些数据表明E2-17G顺式抑制谷胱甘肽的小管转运，因此通过抑制BSIF而有助于胆汁淤积作用。
Estradiol-17beta-D-glucuronide (E2-17G) induces an acute but reversible inhibition of bile flow after its intravenous administration to rats, due in part to the endocytic retrieval of the canalicular multidrug resistance-associated transporter protein 2 and the bile salt export pump, transporters that contribute to bile flow. Decreased bile salt-independent bile flow (BSIF) is also involved and persists during the phase of recovery from cholestasis. Because glutathione and HCO3- are major contributors to BSIF, we evaluated changes in their biliary excretion and the hepatic content of total glutathione during E2-17G-induced cholestasis. E2-17G acutely decreased bile flow and biliary excretion of total glutathione by about 80%; glutathione excretion was still inhibited at 80 min and 120 min, even though bile flow was partially and totally restored, respectively. Neither liver glutathione content nor the proportions of oxidized glutathione in bile and liver were affected by E2-17G at any time. HCO3- concentrations in bile were unchanged, so that secretion paralleled variations in bile flow. In the isolated perfused liver, addition of E2-17G decreased both bile flow and the biliary concentration of glutathione, whereas addition of its noncholestatic isomer estradiol-3-D-glucuronide (E2-3G) did not inhibit bile flow, but significantly reduced the concentration of glutathione in bile. The bile:liver concentration ratios of glutathione were significantly decreased in vivo by E2-17G and in the perfused liver by E2-17G and E2-3G. These data indicate that E2-17G cis-inhibits the canalicular transport of glutathione and thus contributes to the cholestatic effect by inhibiting BSIF.