Polygoni Multiflori Radix derived anthraquinones alter bile acid disposition in sandwich-cultured rat hepatocytes
Polygoni Multiflori Radix derived anthraquinones alter bile acid disposition in sandwich-cultured rat hepatocytes
复制标题
何首乌衍生的蒽醌改变三明治培养的大鼠肝细胞中胆汁酸的分布
DOI：
10.1016/j.tiv.2017.01.022
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发表时间：
2017-04-01
影响因子：
3.2
通讯作者：
Huang, Jiangeng
中科院分区：
文献类型：
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作者：
Kang, Li;Si, Luqin;Huang, Jiangeng
近年来，葛根相关的肝脏不良反应报道较多。PMR中富含的蒽醌类化合物如大黄素、大黄酚、大黄素甲醚等具有肝毒性。本研究采用体外培养的大鼠肝细胞（SCRHs），研究了单独和联合应用蒽醌对内源性胆汁酸（BA）和外源性探针底物氘标记牛磺胆酸（d（5）-TCA）、甘氨鹅脱氧胆酸（d（4）GCDCA）和5（和6）-羧基-2 '，7'-二氯荧光素（CDF）的处置的影响。大黄素和thrysophanol分别显著抑制胆盐输出泵和多药耐药相关蛋白2（Mrp 2），表现为d（5）-TCA和CDF的胆汁排泄指数（BEI）降低。此外，基底外侧外排转运蛋白被所有单独和组合的AQs抑制。因此，细胞积累的总的和特定的内源性BA显着升高，由单独的或组合的单独的AQ。此外，AQs在基因和蛋白水平上下调Mrps是SCRH中BA积累的另一个关键因素。值得注意的是，随后的适应性基因调控，包括减少Ntcp表达，上调Bsep水平，下调Cyp 8b 1，减轻，在一定程度上，但不能阻止毒性BA积累。总之，所有三种感兴趣的AQ都可能通过直接抑制BA转运蛋白以及调节BA转运蛋白和酶的表达来改变BA处置。(C)2017爱思唯尔有限公司版权所有
Hepatic adverse reaction associated with Polygoni Multiflori Radix (PMR) has been frequently reported in recent years. Highly-enriched anthraquinones (AQs) in PMR, such as emodin, chrysophanol and physcion, have been found to be hepatotoxit. In the present study, sandwich-cultured rat hepatocytes (SCRHs) were employed to investigate the effect of individual and combined AQs on the disposition of endogenous bile acids (BAs) and exogenous probe substrates including deuterium-labeled taurocholate (d(5)-TCA), glycochenodeoxycliOlic acid (d(4)GCDCA) and 5 (and 6)-tarboxy-2',7'-dichlorofluorescein (CDF). Emodin and thrysophanol significantly inhibited bile salt export pump and multidrug resistance-associated protein 2 (Mrp2), respectively, as evidenced by decreased biliary excretion index (BEI) of d(5)-TCA and CDF. Moreover, basolateral efflux transporters were inhibited by all individual and combined AQs. As a result, cellular accumulation of total and specific endogenous BAs were significantly elevated by individual AQs, alone or combined. In addition, down-regulation of Mrps in both gene and protein levels by AQs served as another critical contributing factor for BA accumulation in SCRHs. To be noted, subsequent adaptive gene regulation, including reduced Ntcp expression, upregulated Bsep levels, and downregulated Cyp8b1, alleviated, to a certain extent, but not prevented from toxic BA accumulation. In summary, all three AQs of interest are likely to alter BA disposition through direct inhibition of BA transporters as well as regulated expression of BA transporters and enzymes. (C) 2017 Elsevier Ltd. All rights reserved.