Basal efflux of bile acids contributes to drug-induced bile acid-dependent hepatocyte toxicity in rat sandwich-cultured hepatocytes.
Basal efflux of bile acids contributes to drug-induced bile acid-dependent hepatocyte toxicity in rat sandwich-cultured hepatocytes.
复制标题
DOI：
10.1016/j.tiv.2015.06.004
复制
发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Takeshi Susukida;Shuichi Sekine;Eiichiro Ogimura;Shigeki Aoki;K. Oizumi;T. Horie;Kousei Ito
中科院分区：
文献类型：
--
作者：
Takeshi Susukida;Shuichi Sekine;Eiichiro Ogimura;Shigeki Aoki;K. Oizumi;T. Horie;Kousei Ito
胆盐输出泵（BSEP或Bsep）作为一种顶端转运蛋白，将胆汁酸（BA）从肝细胞中清除到胆汁中。BSEP或Bsep抑制剂引起BA滞留，这被认为是胆汁淤积性药物诱导的肝损伤的潜在机制。我们以前报道了一种方法，以评估BSEP介导的BA依赖性肝细胞毒性，通过使用体外培养的肝细胞（SCH）。然而，基础外排转运蛋白，包括多药耐药相关蛋白（MRP或Mrp）3和4，也参与BA外排。本研究探讨了基础外排转运蛋白对大鼠SCH中BA依赖性肝细胞毒性的贡献。10 μM环孢素A（CsA）可有效抑制[3H]牛磺胆酸（TC）的顶端外排，随后抑制基础[3H]TC外排，而MK 571同时抑制顶端和基础[3H]TC外排。CsA诱导的BA依赖性肝细胞毒性在10 μM CsA时最多为30%，在50 μM时最多为60%，而MK 571在≥50 μM浓度时加重肝细胞毒性。奎尼丁只抑制基础[3H]TC流出，并显示BA依赖性肝细胞毒性大鼠SCH。因此，抑制基础外排转运蛋白以及Bsep可能会沉淀BA依赖性肝细胞毒性大鼠SCH。
The bile salt export pump (BSEP or Bsep) functions as an apical transporter to eliminate bile acids (BAs) from hepatocytes into the bile. BSEP or Bsep inhibitors engender BA retention, suggested as an underlying mechanism of cholestatic drug-induced liver injury. We previously reported a method to evaluate BSEP-mediated BA-dependent hepatocyte toxicity by using sandwich-cultured hepatocytes (SCHs). However, basal efflux transporters, including multidrug resistance-associated proteins (MRP or Mrp) 3 and 4, also participate in BA efflux. This study examined the contribution of basal efflux transporters to BA-dependent hepatocyte toxicity in rat SCHs. The apical efflux of [3H]taurocholic acid (TC) was potently inhibited by 10 μM cyclosporine A (CsA), with later inhibition of basal [3H]TC efflux, while MK571 simultaneously inhibited both apical and basal [3H]TC efflux. CsA-induced BA-dependent hepatocyte toxicity was 30% at most at 10 μM CsA and ∼60% at 50 μM, while MK571 exacerbated hepatocyte toxicity at concentrations of ≥50 μM. Quinidine inhibited only basal [3H]TC efflux and showed BA-dependent hepatocyte toxicity in rat SCHs. Hence, inhibition of basal efflux transporters as well as Bsep may precipitate BA-dependent hepatocyte toxicity in rat SCHs.