Zhang Aijie, Jia Yongming, Xu Qinghan, Wang Changyuan, Liu Qi, Meng Qiang, Peng Jinyong, Sun Huijun, Sun Pengyuan, Huo Xiaokui, Liu Kexin
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China.
Toxicol Appl Pharmacol. 2016 Aug 15;305:127-135. doi: 10.1016/j.taap.2016.06.019. Epub 2016 Jun 15.
Alpha-naphthylisothiocyanate (ANIT) is a toxicant that is widely used in rodents to model human intrahepatic cholestasis. The aim of the study is to investigate whether effects of dioscin on ANIT-induced cholestasis are related to changes in expression of hepatic transporters in rats. Effects of dioscin on cholestasis were examined by histology and biochemical marker levels. The functional changes of hepatic transporters were determined by in vitro, in situ and in vivo. qRT-PCR and western blot were used to assess the expression of hepatic transporters in cholestatic rats. Dioscin administration could ameliorate cholestasis, as evidenced by reduced biochemical markers as well as improved liver pathology. The uptakes of organic anion transporting polypeptide (Oatp) substrates were altered in liver uptake index in vivo, perfused rat liver in situ and isolated rat hepatocytes in vitro in cholestasis rats. qRT-PCR and western blot analysis indicated co-treatment of ANIT with dioscin prevented the adaptive down-regulation of Oatp1a1, 1b2, and prompted the up-regulation of Oatp1a4, multidrug resistance-associated protein (Mrp) 2 and bile salt export pump (Bsep). In addition, concerted effects on Mrp2 and Bsep occurred through up-regulation of small heterodimer partner by activating farnesoid X receptor. Dioscin might prevent impairment of hepatic function by restoring hepatic transporter expression.
α-萘基异硫氰酸酯（ANIT）是一种广泛用于啮齿动物以模拟人类肝内胆汁淤积的毒物。本研究的目的是探讨薯蓣皂苷对ANIT诱导的胆汁淤积的影响是否与大鼠肝脏转运体表达的变化有关。通过组织学和生化标志物水平检测薯蓣皂苷对胆汁淤积的影响。通过体外、原位和体内实验确定肝脏转运体的功能变化。采用qRT-PCR和western blot检测胆汁淤积大鼠肝脏转运体的表达。给予薯蓣皂苷可改善胆汁淤积，表现为生化标志物降低以及肝脏病理改善。在胆汁淤积大鼠体内、原位灌注大鼠肝脏和体外分离的大鼠肝细胞中，有机阴离子转运多肽（Oatp）底物的摄取在肝脏摄取指数中发生改变。qRT-PCR和western blot分析表明，ANIT与薯蓣皂苷联合处理可防止Oatp1a1、1b2的适应性下调，并促使Oatp1a4、多药耐药相关蛋白（Mrp）2和胆盐输出泵（Bsep）上调。此外，通过激活法尼酯X受体上调小异二聚体伴侣，对Mrp2和Bsep产生协同作用。薯蓣皂苷可能通过恢复肝脏转运体表达来预防肝功能损害。
