New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions

doi:10.1007/s11684-019-0690-z

Front. Med.

2020, Vol. 14

Issue (1) : 68-80 https://doi.org/10.1007/s11684-019-0690-z

RESEARCH ARTICLE

New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions

Yuan Gao^1,², Zhilei Wang^2,³, Jinfa Tang⁴, Xiaoyi Liu², Wei Shi^2,⁵, Nan Qin^2,⁵, Xiaoyan Wang⁴, Yu Pang⁶, Ruisheng Li⁷, Yaming Zhang², Jiabo Wang², Ming Niu²(

), Zhaofang Bai²(

), Xiaohe Xiao⁸(

)

¹. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
². China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
³. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
⁴. The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
⁵. School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Jiangxi 330004, China
⁶. National Institutes for Food and Drug Control, Beijing 100050, China
⁷. Research Center for Clinical and Translational Medicine, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China
⁸. Integrative Medical Centre, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China

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Abstract

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-1β, 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.

Keywords Epimedii Folium Psoraleae Fructus idiosyncratic hepatotoxicity traditional Chinese medicine incompatibility

Corresponding Author(s): Ming Niu,Zhaofang Bai,Xiaohe Xiao

Just Accepted Date: 31 January 2019 Online First Date: 27 March 2019 Issue Date: 02 March 2020

Cite this article:

Yuan Gao,Zhilei Wang,Jinfa Tang, et al. New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions[J]. Front. Med., 2020, 14(1): 68-80.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0690-z
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I1/68

Fig.1 PF, EF, and PE can induce liver injury in LPS-treated rats. (A) Serum ALT activity in rats co-treated with EF, PF, or PE (normal saline or LPS-treated rats). (B) Serum AST activity in rats co-treated with EF, PF, or PE (normal saline- or LPS-treated rats). * P< 0.001, compared with that in the model group. (C) Typical histopathological section photographs of rat liver specimens for HE analysis (magnification 200×).

Fig.2 Positive TUNEL staining (indicative of cell apoptosis) was observed in liver tissues. A representative photomicrograph at 200× magnification is shown. Liver sections were stained for TUNEL (green) and nuclei (blue).*P<0.05, **P<0.001, compared with those in the model group.

Fig.3 Effect of PF, EF, or PE on inﬂammatory cytokines. (A) plasma concentrations of TNF-α; (B) plasma concentrations of IL-1β; (C) plasma concentrations of IL-6; (D) plasma concentrations of IFN-g. Mod, PL, EL, and PEL groups (n = 10); Con, PF, EF, and PE groups (n = 6); *P< 0.05, **P< 0.01, ***P< 0.001, compared with those in the model group. ^###P<0.001, compared with that in the control group.

Fig.4 Correlation analysis between metabolites and immune factors in different groups. (A) Variations in the trends of RT19.35_M/Z330.276, RT17.14_M/Z703.572, RT7.93_M/Z560.3096, and RT13.96_M/Z301.297 are shown. *P<0.05, **P<0.01, ***P<0.001, compared with those in the control group. (B) Class 1–5 represents the control, model, PL, EL, and PEL groups.

Fig.5 Schematic diagram of the disturbed metabolic pathway. The size of the ball represents the relative degree of change between groups; the color of the ball represents the tendency of compounds to increase or decrease.

Tab.1 Differentially identified metabolites for discrimination among the control, model, PL, EL, and PEL groups

Fig.6 Schematic diagram of liver injury induced by EF, PF, and PE under immunological stress conditions. (A) EF, PF or PE cannot induce liver injury under normal conditions. (B) EF, PF, or PE can lead to a serious liver injury under immunological stress conditions. The main mechanism of liver injury induced by EF, PF, and PE may be different: EF may regulate immune inflammation to induce liver injury; PF may regulate metabolism to induce liver injury; and PE may lead to a more serious liver injury by the comprehensive regulation of immune inflammation and metabolic dysfunction.

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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. Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum[J]. Front. Med., 2017, 11(2): 253-265.

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