Polygoni Multiflori Radix derived anthraquinones alter bile acid disposition in sandwich-cultured rat hepatocytes. (April 2017)

• Record Type: Journal Article
• Authors: Kang, Li; Si, Luqin; Rao, Jing; Li, Dan; Wu, Ya; Wu, Sanlan; Wu, Minghui; He, Sijie; Zhu, Wenwen; Wu, Yang; Xu, Jiaqiang; Li, Gao; Huang, Jiangeng
• Is Part Of: Toxicology in vitro. Volume 40(2017)
• Page Start: 313
• Page End: 323
• Publication Date: 2017-04
• Subjects: Polygoni Multiflori Radix -- Anthraquinones -- Bile acids -- Hepatotoxicity -- Sandwich-cultured rat hepatocytes; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2017.01.022
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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 hepatotoxic. 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), glycochenodeoxycholic acid ( d 4 -GCDCA) and 5 (and 6)-carboxy-2′, 7′-dichlorofluorescein (CDF). Emodin and chrysophanol 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. Graphical abstract: Highlights: Anthraquinones alter bile acid disposition in sandwich cultured rat hepatocytes. Anthraquinones regulate expression of bile acid transporters and enzymes. Emodin and chrysophanol inhibit canalicular bile acid efflux transporters. Inhibition on basolateral efflux transporters exacerbates bile acid retention.