2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside enhances the hepatotoxicity of emodin in vitro and in vivo

被引:7
作者
Li, Dan [1 ]
Song, Qianbo [1 ]
Ji, Xiaoyu [1 ]
Lyu, Yuanfeng [1 ]
Lai, Yuen Sze [1 ]
Zuo, Zhong [1 ]
机构
[1] Chinese Univ Hong Kong, Fac Med, Sch Pharm, Shatin, Hong Kong, Peoples R China
关键词
Polygoni Multiflori Radix; Emodin; 2,3,5,4 '-tetrahydroxystilbene-2-O-beta-D-glucopyranoside; Hepatotoxicity; Bile acid homeostasis; POLYGONI-MULTIFLORI RADIX; SANDWICH-CULTURED HEPATOCYTES; INDUCED LIVER-INJURY; BILE-ACID DISPOSITION; DRUG-DRUG INTERACTION; ACUTE HEPATITIS; CELL APOPTOSIS; IDIOSYNCRATIC HEPATOTOXICITY; STILBENE GLUCOSIDE; KEY ENZYMES;
D O I
10.1016/j.toxlet.2022.06.008
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
Herb-induced liver injury results from the interplay between the herb and host with the herbal components serving as the major origin for hepatotoxicity. Although Polygoni Multiflori Radix (PMR) has been frequently reported to induce liver injury, contributions of its major components such as emodin, emodin-8-O-beta-D-glucopyranoside, physcion and 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucopyranoside (TSG) towards its hepatotoxicity have not been clearly identified. Our initial cytotoxicity screenings of the major PMR components using rat hepatocytes identified emodin as the most toxic. Subsequently, the bile acid homeostasis-related mechanisms of emodin and its combination treatment with TSG in PMR-associated liver injury were explored in sandwich cultured rat hepatocytes (SCRH) and verified in rats. In SCRH, emodin was found to be able to induce total bile acid accumulation in a dose-dependent manner. In both SCRH and rats, the presence of TSG significantly enhanced the hepatotoxicity of emodin via i) increasing its hepatic exposure by inhibiting its glucuronidation mediated metabolism; ii) enhancing its disruption on bile acid homeostasis through amplifying its inhibition on bile acid efflux transporters and its up-regulation on bile acids synthesis enzymes; iii) enhancing its apoptosis. Our study for the first time demonstrated the critical role of the combination treatment with emodin and TSG in PMR-induced liver injury.
引用
收藏
页码:74 / 85
页数:12
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