Huang L, Smit J W, Meijer D K, Vore M
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305, USA.
Hepatology. 2000 Jul;32(1):66-72. doi: 10.1053/jhep.2000.8263.
The present study evaluates the roles of the multidrug resistance-1 P-glycoprotein, Mdr1a/1b, the bile salt export pump (Bsep), and the multidrug resistance-associated protein-2 (Mrp2) in mediating cholestasis induced by estradiol-17beta(beta-D-glucuronide) (E(2)17G). Administration of ¿(3)HE(2)17G (18 nmol/g body weight) gave a similar degree of cholestasis and biliary excretion of E(2)17G-equivalents in wild-type and Mdr1a(-/-)/1b(-/-) mice. When expressed in Sf9 cells, Bsep-mediated adenosine triphosphate (ATP)-dependent transport of taurocholate (TC, 1 micromol/L) in membrane vesicles was 110% +/- 12.5% and 108% +/- 17.3% of control in the presence of 10 and 50 micromol/L E(2)17G, respectively, whereas in rat canalicular membrane, both E(2)17G and the choleretic estradiol-3-beta-D-glucuronide (E(2)3G) inhibited ATP-dependent transport of TC to the same extent. Infusion of ¿(3)HE(2)17G (24 micromol) did not induce cholestasis in Mrp2-deficient TR(-) rats whereas 2 micromol of ¿(3)HE(2)17G inhibited bile flow by 51% in control Wistar rats. The maximal biliary concentration of E(2)17G was 3.5 and 2.5 mmol/L in control and TR(-) rats, respectively. However, 2.2 mmol/L of E(2)17G in bile is associated with inhibition of bile flow in control rats. These data show that (1) Mdr1a/1b are not essential for E(2)17G-mediated cholestasis, (2) direct inhibition of Bsep-mediated bile acid transport is not the mechanism for E(2)17G cholestasis, and (3) accumulation of E(2)17G in bile alone is not sufficient to induce cholestasis. These data indicate that the process of Mrp2-mediated transport of high concentrations of E(2)17G is essential for its induction of cholestasis.
本研究评估了多药耐药蛋白1（P-糖蛋白，Mdr1a/1b）、胆盐输出泵（Bsep）以及多药耐药相关蛋白2（Mrp2）在介导17β-雌二醇葡萄糖醛酸苷（E(2)17G）诱导的胆汁淤积中的作用。给野生型和Mdr1a(-/-)/1b(-/-)小鼠注射³H-E(2)17G（18 nmol/g体重）后，胆汁淤积程度以及E(2)17G等效物的胆汁排泄情况相似。当在Sf9细胞中表达时，在存在10和50 μmol/L E(2)17G的情况下，Bsep介导的膜囊泡中牛磺胆酸盐（TC，1 μmol/L）的三磷酸腺苷（ATP）依赖性转运分别为对照的110%±12.5%和108%±17.3%，而在大鼠胆小管膜中，E(2)17G和胆汁酸诱导剂雌二醇-3-β-D-葡萄糖醛酸苷（E(2)3G）对TC的ATP依赖性转运的抑制程度相同。给Mrp2缺陷型TR(-)大鼠输注³H-E(2)17G（24 μmol）未诱导胆汁淤积，而给对照Wistar大鼠输注2 μmol³H-E(2)17G可使胆汁流量降低51%。对照大鼠和TR(-)大鼠胆汁中E(2)17G的最大浓度分别为3.5和2.5 mmol/L。然而，对照大鼠胆汁中2.2 mmol/L的E(2)17G与胆汁流量抑制相关。这些数据表明：（1）Mdr1a/1b对E(2)17G介导的胆汁淤积并非必不可少；（２）直接抑制Bsep介导的胆汁酸转运不是E(2)17G胆汁淤积的机制；（３）仅胆汁中E(2)17G的蓄积不足以诱导胆汁淤积。这些数据表明，Mrp2介导的高浓度E(2)17G转运过程对其诱导胆汁淤积至关重要。
