Cheng Yaofeng, Chen Shenjue, Freeden Chris, Chen Weiqi, Zhang Yueping, Abraham Pamela, Nelson David M, Humphreys W Griffith, Gan Jinping, Lai Yurong
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey.
J Pharmacol Exp Ther. 2017 Sep;362(3):385-394. doi: 10.1124/jpet.117.242370. Epub 2017 Jun 23.
The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats.
通过抑制胆盐输出泵（BSEP）干扰胆汁酸分泌是曲格列酮（TGZ）诱导肝毒性的机制之一。在此，我们研究了单次或重复口服TGZ（200mg/kg/天，共7天）对野生型（WT）和Bsep基因敲除（KO）大鼠胆汁酸稳态的影响。口服给药后，WT和KO大鼠的TGZ血浆暴露量无差异，且在第1天和第7天相似。然而，由于TS胆汁排泄增加，KO大鼠中主要代谢物硫酸曲格列酮（TS）的血浆暴露量在第1天和第7天分别比WT大鼠低7.6倍和9.3倍。由于Bsep基因敲除，KO大鼠中多药耐药相关蛋白2（Mrp2）、Mrp3、Mrp4、Mdr1、乳腺癌耐药蛋白（Bcrp）、牛磺胆酸钠共转运多肽、小异二聚体伴侣和Sult2A1的mRNA水平发生了显著改变。在每日给予TGZ七次后，WT和KO大鼠的Cyp7A1均显著增加。在溶剂对照组中，与WT大鼠相比，KO大鼠个体胆汁酸的血浆暴露量呈现出不同的变化。给予TGZ的WT大鼠在第1天血浆中多种胆汁酸种类增加，提示Bsep受到抑制。相反，这些变化在第7天恢复到基线水平。在KO大鼠中，给予七次TGZ后观察到大多数胆汁酸的改变。总体而言，大鼠胆汁酸稳态通过胆汁酸合成和转运来调节，以应对Bsep缺乏和TGZ抑制。此外，我们的研究首次证明重复给予TGZ可上调大鼠的Cyp7A1。
