Mottino Aldo D, Veggi Luis M, Wood Marcie, Román Joyce M Vélez, Vore Mary
Institute of Experimental Physiology, School of Biochemical and Pharmaceutical Sciences, Rosario, Argentina.
J Pharmacol Exp Ther. 2003 Oct;307(1):306-13. doi: 10.1124/jpet.103.054544. Epub 2003 Jul 31.
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.
17β - 雌二醇 - D - 葡萄糖醛酸苷（E2 - 17G）静脉注射给大鼠后可诱导胆汁流量出现急性但可逆的抑制，部分原因是胆小管多药耐药相关转运蛋白2和胆汁盐输出泵的内吞回收，这些转运蛋白对胆汁流量有贡献。胆汁盐非依赖性胆汁流量（BSIF）的降低也参与其中，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，我们评估了在E2 - 17G诱导的胆汁淤积期间它们的胆汁排泄变化以及肝脏中总谷胱甘肽的含量。E2 - 17G急性降低胆汁流量和总谷胱甘肽的胆汁排泄约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分钟时仍受到抑制。E2 - 17G在任何时候都不影响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。胆汁中的HCO3 - 浓度未发生变化，因此其分泌与胆汁流量的变化平行。在离体灌注肝脏中，添加E2 - 17G可降低胆汁流量和胆汁中谷胱甘肽的浓度，而添加其非胆汁淤积性异构体雌二醇 - 3 - D - 葡萄糖醛酸苷（E2 - 3G）并不抑制胆汁流量，但显著降低胆汁中谷胱甘肽的浓度。在体内，E2 - 17G使谷胱甘肽的胆汁：肝脏浓度比显著降低，在灌注肝脏中，E2 - 17G和E2 - 3G也使其降低。这些数据表明，E2 - 17G顺式抑制谷胱甘肽的胆小管转运，从而通过抑制BSIF导致胆汁淤积效应。
