Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection.
Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection.
复制标题
DOI：
--
复制
发表时间：
1995-02
期刊：
影响因子：
--
通讯作者：
R. Botla;J. Spivey;H. Aguilar;S. Bronk;G. Gores
中科院分区：
文献类型：
--
作者：
R. Botla;J. Spivey;H. Aguilar;S. Bronk;G. Gores
熊去氧胆酸盐（UDCA）是一种亲水性胆汁盐，可改善毒性胆汁盐引起的肝细胞损伤，并用于治疗胆汁淤积性肝病。然而，胆盐介导的肝细胞坏死和UDCA细胞保护的机制仍不清楚。肝细胞坏死被认为是由线粒体膜通透性转换（MMPT）引起的。因此，我们研究的目的是确定毒性胆汁盐甘氨鹅去氧胆酸盐（GCDC）是否诱导MMPT，如果是，UDCA是否阻止胆汁盐诱导的MMPT。在分离的大鼠肝线粒体中评估MMPT。在分离的大鼠肝细胞中测量细胞活力。GCDC以剂量依赖性方式诱导MMPT。GCDC诱导的MMPT被环孢菌素A加三氟拉嗪（已知的MMPT抑制剂）部分阻断。UDCA还抑制GCDC诱导的MMPT，并通过氧化苯砷（MMPT的既定介质）部分阻断MMPT。UDCA或环孢菌素A加三氟拉嗪可防止GCDC治疗期间肝细胞活力丧失。总之，GCDC诱导MMPT;这一发现为有毒胆盐引起的生物能量形式的细胞坏死提供了物理化学解释。UDCA的细胞保护作用部分可能是由于抑制胆盐诱导的MMPT。
Ursodeoxycholate (UDCA), a hydrophilic bile salt, ameliorates hepatocellular injury by toxic bile salts and is used to treat cholestatic liver disease. However, the mechanisms of bile salt-mediated hepatocyte necrosis and UDCA cytoprotection remain unclear. Hepatocyte necrosis is thought to be caused by the mitochondrial membrane permeability transition (MMPT). Thus, the aims of our study were to determine if a toxic bile salt, glycochenodeoxycholate (GCDC) induces the MMPT and if so, whether UDCA prevents the bile salt-induced MMPT. The MMPT was assessed in isolated rat liver mitochondria. Cell viability was measured in isolated rat hepatocytes. GCDC induced the MMPT in a dose-dependent manner. The GCDC-induced MMPT was partially blocked by cyclosporin A plus trifluoperazine, known inhibitors of the MMPT. UDCA also inhibited the GCDC-induced MMPT, and partially blocked the MMPT by phenylarsene oxide, an established mediator of the MMPT. UDCA or cyclosporin A plus trifluoperazine protected against loss of hepatocyte viability during treatment with GCDC. In conclusion, GCDC induces a MMPT; a finding providing a physicochemical explanation for the bioenergetic form of cell necrosis caused by toxic bile salts. UDCA cytoprotection may, in part, be due to inhibition of the bile salt-induced MMPT.