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Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum

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《医学前沿（英文）》 2017年 第11卷 第2期   页码 253-265 doi: 10.1007/s11684-017-0508-9

摘要：

The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent “knock-out” and “knock-in” strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

关键词： Polygonum multiflorum     idiosyncratic hepatotoxicity     metabolomics     stilbene     cis-transisomerization    

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New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity

Yuan Gao, Zhilei Wang, Jinfa Tang, Xiaoyi Liu, Wei Shi, Nan Qin, Xiaoyan Wang, Yu Pang, Ruisheng Li, Yaming Zhang, Jiabo Wang, Ming Niu, Zhaofang Bai, Xiaohe Xiao

《医学前沿（英文）》 2020年 第14卷 第1期   页码 68-80 doi: 10.1007/s11684-019-0690-z

摘要： Epimedii Folium (EF) combined with Psoraleae Fructus (PF) is a common modern preparation, but liver injury caused by Chinese patent medicine preparations containing EF and PF has been frequently reported in recent years. Zhuangguguanjiewan pills (ZGW), which contain EF and PF, could induce immune idiosyncratic liver injury according to clinical case reports and a nonhepatotoxic dose of lipopolysaccharide (LPS) model. This present study evaluated the liver injury induced by EF or PF alone or in combination and investigated the related mechanism by using the LPS model. Liver function indexes and pathological results showed that either EF or PF alone or in combination led to liver injury in normal rats; however, EF or PF alone could lead to liver injury in LPS-treated rats. Moreover, EF combined with PF could induce a greater degree of injury than that caused by EF or PF alone in LPS-treated rats. Furthermore, EF or PF alone or in combination enhanced the LPS-stimulated inflammatory cytokine production, implying that IL-1 , which is processed and released by activating the NLRP3 inflammasome, is a specific indicator of EF-induced immune idiosyncratic hepatotoxicity. Thus, EF may induce liver injury through enhancing the LPS-mediated proinflammatory cytokine production and activating the NLRP3 inflammasome. In addition, the metabolomics analysis results showed that PF affected more metabolites in glycerophospholipid and sphingolipid metabolic pathways compared with EF in LPS model, suggesting that PF increased the responsiveness of the liver to LPS or other inflammatory mediators via modulation of multiple metabolic pathways. Therefore, EF and PF combination indicates traditional Chinese medicine incompatibility, considering that it induces idiosyncratic hepatotoxicity under immunological stress conditions.

关键词： Epimedii Folium     Psoraleae Fructus     idiosyncratic hepatotoxicity     traditional Chinese medicine incompatibility    

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Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb,

Chunyu Li, Ming Niu, Zhaofang Bai, Congen Zhang, Yanling Zhao, Ruiyu Li, Can Tu, Huifang Li, Jing Jing, Yakun Meng, Zhijie Ma, Wuwen Feng, Jinfa Tang, Yun Zhu, Jinjie Li, Xiaoya Shang, Zhengsheng Zou, Xiaohe Xiao, Jiabo Wang

《医学前沿（英文）》 2021年 第15卷 第2期   页码 330-332 doi: 10.1007/s11684-020-0819-0

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Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratichepatotoxicity

Nan Qin, Guang Xu, Yan Wang, Xiaoyan Zhan, Yuan Gao, Zhilei Wang, Shubin Fu, Wei Shi, Xiaorong Hou, Chunyu Wang, Ruisheng Li, Yan Liu, Jiabo Wang, Haiping Zhao, Xiaohe Xiao, Zhaofang Bai

《医学前沿（英文）》 2021年 第15卷 第4期   页码 594-607 doi: 10.1007/s11684-020-0809-2

摘要： Psoraleae Fructus (PF) is a well-known traditional herbal medicine in China, and it is widely used for osteoporosis, vitiligo, and other diseases in clinical settings. However, liver injury caused by PF and its preparations has been frequently reported in recent years. Our previous studies have demonstrated that PF could cause idiosyncratic drug-induced liver injury (IDILI), but the mechanism underlying its hepatotoxicity remains unclear. This paper reports that bavachin isolated from PF enhances the specific stimuli-induced activation of the NLRP3 inflammasome and leads to hepatotoxicity. Bavachin boosts the secretion of IL-1β and caspase-1 caused by ATP or nigericin but not those induced by poly(I:C), monosodium urate crystal, or intracellular lipopolysaccharide. Bavachin does not affect AIM2 or NLRC4 inflammasome activation. Mechanistically, bavachin specifically increases the production of nigericin-induced mitochondrial reactive oxygen species among the most important upstream events in the activation of the NLRP3 inflammasome. Bavachin increases the levels of aspartate transaminase and alanine aminotransferase in serum and hepatocyte injury accompanied by the secretion of IL-1β via a mouse model of lipopolysaccharide-mediated susceptibility to IDILI. These results suggest that bavachin specifically enhances the ATP- or nigericin-induced activation of the NLRP3 inflammasome. Bavachin also potentially contributes to PF-induced idiosyncratic hepatotoxicity. Moreover, bavachin and PF should be evaded among patients with diseases linked to the ATP- or nigericin-mediated activation of the NLRP3 inflammasome, which may be a dangerous factor for liver injury.

关键词： Psoraleae Fructus     bavachin     idiosyncratic drug-induced liver injury     caspase-1     IL-1β     NLRP3 inflammasome    

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标题 作者 时间 类型 操作

Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum

null

期刊论文

New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity

Yuan Gao, Zhilei Wang, Jinfa Tang, Xiaoyi Liu, Wei Shi, Nan Qin, Xiaoyan Wang, Yu Pang, Ruisheng Li, Yaming Zhang, Jiabo Wang, Ming Niu, Zhaofang Bai, Xiaohe Xiao

期刊论文

Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb,

Chunyu Li, Ming Niu, Zhaofang Bai, Congen Zhang, Yanling Zhao, Ruiyu Li, Can Tu, Huifang Li, Jing Jing, Yakun Meng, Zhijie Ma, Wuwen Feng, Jinfa Tang, Yun Zhu, Jinjie Li, Xiaoya Shang, Zhengsheng Zou, Xiaohe Xiao, Jiabo Wang

期刊论文

Bavachin enhances NLRP3 inflammasome activation induced by ATP or nigericin and causes idiosyncratichepatotoxicity

Nan Qin, Guang Xu, Yan Wang, Xiaoyan Zhan, Yuan Gao, Zhilei Wang, Shubin Fu, Wei Shi, Xiaorong Hou, Chunyu Wang, Ruisheng Li, Yan Liu, Jiabo Wang, Haiping Zhao, Xiaohe Xiao, Zhaofang Bai

期刊论文