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

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

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81874368 and 81630100), the Beijing Nova Program (No. Z181100006218001), the National Key Technology R&D Program (No. 2015ZX 09501-004-001-008), the National Key R&D Program of China (No. 2018YFC1707000), and the National TCM Industry Science and Technology Program (No. 201507004-4-2).

Compliance with ethics guidelines

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, and Xiaohe Xiao declare that they have no conflicts of interest to disclose. The study was approved by the Experimental Animal Center of the Fifth Medical Centre, Chinese PLA (People’s Liberation Army) General Hospital in Beijing, China. All animal experiments complied with the animal welfare and ethics guidelines. Male Sprague–Dawley rats (180–220 g) were obtained from the Laboratory Animal Center of the Academy of Military Medical Sciences (License No. SCXK2012-004). All procedures followed were in accordance with the ethical standards of the Ethics Committee in the Fifth Medical Centre, Chinese PLA (People’s Liberation Army) General Hospital and the Helsinki Declaration of 1975.

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