Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol‐induced cholestasis in the rat
Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol‐induced cholestasis in the rat
复制标题
胆小管有机阴离子转运蛋白（Mrp2/cmoat）活性受损并不是炔雌醇引起的大鼠胆汁淤积的主要原因
作者：
N. R. Koopen;H. Wolters;R. Havinga;R. Vonk;P. Jansen;Michael Müller;F. Kuipers
为检验以下假设：胆小管有机阴离子转运系统mrp 2（cmoat）活性受损是17α-乙炔基甜菜碱（EE）诱导的大鼠肝内胆汁淤积症病因学中的关键事件，对雄性正常Wistar（NW）和mrp 2缺陷型Groningen Yellow/转运缺陷型Wistar（戈伊/TR−）大鼠给予EE（5 mg/kg，每日皮下注射）。EE处理后，戈伊/TR−大鼠血浆胆红素水平升高，3天内从65 ± 8.4 μmol/L升高至183 ± 22.7 μmol/L，而NW大鼠的胆红素水平未受影响。NW大鼠的胆汁胆红素分泌增加1.5倍，但戈伊/TR−大鼠的胆汁胆红素分泌保持不变。两种菌株的血浆胆盐浓度保持不变，尽管肝窦Na+-牛磺胆酸盐共转运蛋白（ntcp）水平显著降低。内源性胆盐的胆汁分泌在两种菌株中均不受影响。治疗3天后，发现NW大鼠肝质膜中mrp 2水平明显降低。在NW大鼠中，胆汁流量的非胆盐依赖性分数（BSIF）从2.6 μL/min/100 g体重降至2.0 μL/min/100 g体重，同时胆汁谷胱甘肽分泌减少62%。在戈伊/TR−大鼠中缺乏mrp 2和胆汁谷胱甘肽并不能阻止EE-胆汁淤积的诱导; BSIF的类似绝对降低，即，1.1 - 0.6 μL/min/100 g体重。EE治疗导致mrp 2底物二溴硫代酞（DBSP）的最大胆汁分泌率（SRM）降低，NW大鼠从1，040 nmol/min/100 g体重（−38%）降至695 nmol/min/100 g体重（−46%），戈伊/TR−大鼠从615 nmol/min/100 g体重（−46%）降至327 nmol/min/100 g体重（−46%）。这些结果表明，mrp 2活性和/或胆汁谷胱甘肽分泌的抑制不是EE诱导的大鼠胆汁淤积的主要原因。数据表明，胆红素和相关有机阴离子的胆汁分泌存在替代途径，这些途径也受到EE的影响。
To test the hypothesis that impaired activity of the bile canalicular organic anion transporting system mrp2 (cmoat) is a key event in the etiology of 17α‐ethinylestradiol (EE)‐induced intrahepatic cholestasis in rats, EE (5 mg/kg subcutaneously daily) was administered to male normal Wistar (NW) and mrp2‐deficient Groningen Yellow/Transport‐deficient Wistar (GY/TR−) rats. Elevated plasma bilirubin levels in GY/TR− rats increased upon EE‐treatment from 65 ± 8.4 μmol/L to 183 ± 22.7 μmol/L within 3 days, whereas bilirubin levels remained unaffected in NW rats. Biliary bilirubin secretion was 1.5‐fold increased in NW rats but remained unaltered in GY/TR− rats. Plasma bile salt concentrations remained unchanged in both strains, although hepatic levels of the sinusoidal Na+‐taurocholate cotransporting protein (ntcp) were markedly reduced. Biliary secretion of endogenous bile salt was not affected in either strain. A clear reduction of mrp2 levels in liver plasma membranes of NW rats was found after 3 days of treatment. The bile salt–independent fraction of bile flow (BSIF) was reduced from 2.6 to 2.0 μL/min/100 g body weight in NW rats with a concomitant 62% reduction of biliary glutathione secretion. The absence of mrp2 and biliary glutathione in GY/TR− rats did not prevent induction of EE‐cholestasis; a similar absolute reduction of BSIF, i.e., from 1.1 to 0.6 μL/min/100 g body weight, was found in these animals. EE treatment caused a reduction of the maximal biliary secretory rate (SRM) of the mrp2 substrate, dibromosulphthalein (DBSP), from 1,040 to 695 nmol/min/100 g body weight (−38%) in NW rats and from 615 to 327 nmol/min/100 g body weight (−46%) in GY/TR− rats. These results demonstrate that inhibition of mrp2 activity and/or biliary glutathione secretion is not the main cause of EE‐induced cholestasis in rats. The data indicate that alternative pathways exist for the biliary secretion of bilirubin and related organic anions that are also affected by EE.
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