Polygoni Multiflori Radix derived anthraquinones alter bile acid disposition in sandwich-cultured rat hepatocytes.
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 (d5-TCA), glycochenodeoxycholic acid (d4-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 d5-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.
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Li
L
Kang
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Engineering Research Center for Novel Drug Delivery Systems, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Luqin
L
Si
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Jing
J
Rao
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Dan
D
Li
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Ya
Y
Wu
Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Sanlan
S
Wu
Malcom Randall VA Medical Center, Gainesville, FL 32608, USA.
Minghui
M
Wu
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Sijie
S
He
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Wenwen
W
Zhu
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Yang
Y
Wu
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Jiaqiang
J
Xu
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Engineering Research Center for Novel Drug Delivery Systems, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Gao
G
Li
Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Engineering Research Center for Novel Drug Delivery Systems, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: jiangenghuang@hust.edu.cn.
Jiangeng
J
Huang
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000068676:Fallopia multiflora; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018517:Plant Roots; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley
D018528:ATP-Binding Cassette Transporters; D000880:Anthraquinones; D001647:Bile Acids and Salts; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System
Anthraquinones; Bile acids; Hepatotoxicity; Polygoni Multiflori Radix; Sandwich-cultured rat hepatocytes