Liu L, Yang Y, Li W, Li Y, Jiang X, Wang L
Department of Pharmacy, The Eighth Affiliated Hospital, 575842Sun Yat-sen University, Shenzhen, China.
Department of Clinical Pharmacy and Pharmacy Administration, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, 535321Sichuan University, Chengdu, China.
Hum Exp Toxicol. 2022 Jan-Dec;41:9603271221097365. doi: 10.1177/09603271221097365.
Rifampicin (RFP) induces cholestasis due to long-term tubercular therapy. Impairment of the canalicular bile acids efflux via the bile salt export pump (BSEP) is a well-recognized cause of cholestasis. Tanshinone IIA (TAN IIA) has a protective effect on the liver. However, there are limited studies on the effects of RFP and TAN IIA on BSEP. In present study, we aimed to elucidate the effects of RFP and TAN IIA on BSEP and provide evidence to support the treatment of RFP-induced cholestasis with TAN IIA. Firstly, liver histopathological examination and serum biochemical tests were evaluated in rats. Secondly, we evaluated BSEP expression by qRT-PCR and western blotting to explore whether RFP and TAN IIA influence liver function through BSEP. Thirdly, the accumulation of BSEP substrate taurocholic acid (TCA) in bile ducts was determined to investigate the effects of RFP and TAN IIA on BSEP function. Apparent histopathological alterations and significantly increased serum biomarkers were observed in the RFP group (200 mg/kg), while these changes were attenuated in the combination groups. The mRNA and protein levels of BSEP were decreased by RFP. Whereas TAN IIA reversed the downward regulation of BSEP caused by RFP. And RFP primarily inhibited TCA excretion but co-administration of TAN IIA markedly induced TCA excretion mediated by BSEP. Our findings collectively demonstrated that RFP-induced cholestasis could be related to the inhibition of BSEP, and TAN IIA had the potential to prevent RFP-induced cholestasis by regulating BSEP.
利福平（RFP）因长期用于结核病治疗而导致胆汁淤积。经胆小管胆汁酸通过胆盐输出泵（BSEP）流出受损是胆汁淤积的一个公认原因。丹参酮IIA（TAN IIA）对肝脏有保护作用。然而，关于RFP和TAN IIA对BSEP影响的研究有限。在本研究中，我们旨在阐明RFP和TAN IIA对BSEP的影响，并为用TAN IIA治疗RFP诱导的胆汁淤积提供证据。首先，对大鼠进行肝脏组织病理学检查和血清生化检测。其次，我们通过qRT-PCR和蛋白质印迹法评估BSEP表达，以探讨RFP和TAN IIA是否通过BSEP影响肝功能。第三，测定胆管中BSEP底物牛磺胆酸（TCA）的积累，以研究RFP和TAN IIA对BSEP功能的影响。在RFP组（200mg/kg）中观察到明显的组织病理学改变和血清生物标志物显著增加，而在联合用药组中这些变化有所减轻。RFP降低了BSEP的mRNA和蛋白质水平。而TAN IIA逆转了RFP引起的BSEP下调。并且RFP主要抑制TCA排泄，但TAN IIA的联合给药显著诱导了由BSEP介导的TCA排泄。我们的研究结果共同表明，RFP诱导的胆汁淤积可能与BSEP的抑制有关，而TAN IIA有可能通过调节BSEP来预防RFP诱导的胆汁淤积。
