Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate
Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate
复制标题
DOI：
10.1016/s0300-483x(01)00460-7
复制
发表时间：
2001-10-05
期刊：
影响因子：
4.5
通讯作者：
Gasser, R
中科院分区：
文献类型：
--
作者：
Funk, C;Pantze, M;Gasser, R
曲格列酮是一种治疗2型非胰岛素依赖型糖尿病（NIDDM）的噻唑烷二酮类胰岛素增敏药物。基于越来越多的关于曲格列酮相关肝毒性的报道，人们对曲格列酮及其主要代谢物硫酸曲格列酮的抑胆潜能进行了研究。在离体灌注大鼠肝脏中，曲格列酮（10mum）在60分钟内使胆汁流量减少25%（雌性）至50%（雄性）。两性大鼠单次静脉给予曲格列酮后，血浆胆汁酸浓度迅速且呈剂量依赖性增加，雄性大鼠比雌性大鼠更敏感。与雌性大鼠肝组织相比，雄性大鼠肝组织中硫酸曲格列酮含量高5倍。这种差异是由于硫酸曲格列酮在雄性大鼠肝脏细胞质组分中的形成速度是雌性大鼠肝脏的四倍(Clint分别为132和35 μ min（-1) mg(-1)）。硫酸曲格列酮对两性离体小管大鼠肝质膜制剂中由小管胆汁盐输出泵（Bsep）介导的atp依赖性牛磺胆酸盐转运均有较强的抑制作用（IC50值为0.4 ~ 0.6 muM），而曲格列酮的抑制作用弱10倍（IC50值为3.9 muM）。这种高Bsep抑制电位和硫酸曲格列酮在肝组织中的高效形成和积累，表明硫酸曲格列酮在大鼠小管Bsep水平上与胆汁酸的肝胆输出相互作用的主要原因。这种相互作用也可能潜在地导致男性曲格列酮诱导的肝内胆汁淤积，潜在地促进曲格列酮诱导的肝损伤的形成。(C) 2001爱思唯尔科学爱尔兰有限公司版权所有。
Troglitazone is a thiazolidinedione insulin sensitizer drug for the treatment of type 2 non-insulin-dependent diabetes mellitus (NIDDM). Based on an increasing number of reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone and its major metabolite troglitazone sulfate has been investigated. In isolated perfused rat livers troglitazone (10 muM) reduced the bile flow by 25% (female) to 50% (male) within 60 min. After single intravenous administrations of troglitazone to rats of both genders, rapid and dose-dependent increases in the plasma bile acid concentrations were observed, with male rats being more sensitive than female rats. In male rat liver tissue fivefold higher troglitazone sulfate levels were measured as compared to female rat liver tissue. This difference was due to the formation rate of troglitazone sulfate, which was four times faster in cytosolic fractions of male rat liver as compared to female rat liver (Clint = 132 and 35 mul min(-1) mg(-1), respectively). Troglitazone sulfate strongly inhibited the ATP-dependent taurocholate transport mediated by the canalicular bile salt export pump (Bsep) in isolated canalicular rat liver plasma membrane preparations of both genders (IC50 value of 0.4-0.6 muM), while troglitazone was 10 times less potent (IC50 values of 3.9 muM). This high Bsep inhibition potential and the efficient formation and accumulation of troglitazone sulfate in liver tissue, suggested that troglitazone sulfate was mainly responsible for the interaction with the hepatobiliary export of bile acids at the level of the canalicular Bsep in rats. Such an interaction might lead potentially also in man to a troglitazone-induced intrahepatic cholestasis, potentially contributing to the formation of troglitazone-induced liver injuries. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.