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

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

doi:10.1007/s11684-019-0690-z

Cited by 47 publications

(39 citation statements)

References 51 publications

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“…EF is a commonly used herbal medicine for invigorating the liver and kidney, but the potential hepatotoxicity of EF limits its clinical application. Our previous study indicated that EF could lead to IDILI, which has been con rmed by clinical cases and an LPS-mediated susceptibility mouse model of IDILI [14]. Meanwhile, our data indicate that IL-1β produced by NLRP3 in ammasome activation is a marker for EF-induced idiosyncratic hepatotoxicity.…”

Section: Discussionsupporting

confidence: 59%

“…Our previous studies con rmed that EF could induce liver injury in an LPS-mediated susceptible mouse model of IDILI. In this model, liver injury was accompanied by elevated serum levels of IL-1β [14], so we speculate that components derived from EF may induce liver injury by promoting the formation of NLRP3 in ammasome.…”

Section: Introductionmentioning

confidence: 74%

“…With the widespread use of herbal and dietary supplements (HDS) worldwide, several researches have indicated that traditional Chinese medicine (TCM) herbal and dietary supplements are the leading causes of drug-induced liver injury (DILI), not only in Asian countries but also in western countries [11]. In particular, liver injury induced by TCMs, such as Epimedii Folium, Psoraleae Fructus, Polygonum multi orum and Dictamni Cortex, have been reported frequently in mainland China [12][13][14][15]. Although accumulating evidence has demonstrated that some TCMs could induce IDILI, the mechanism is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Icarisid I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

Gao

et al. 2020

Preprint

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Background Epimedii Folium(EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI. Methods Mouse were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo. Results Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mice model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation. Conclusions Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI.

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Section: Discussionsupporting

confidence: 59%

Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Icarisid I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

Gao

et al. 2020

Preprint

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“…Authors from many countries around the world reported on cases of HILI in connection with the consumption of various herbs, all published since 1993 ( Table 4 ) [ 29 , 37 , 38 , 42 , 48 , 100 , 101 , 102 , 103 , 113 , 115 , 116 , 117 , 118 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 ,…”

Section: Worldwide Publications Of Hili Cases Assessed For Causalimentioning

confidence: 99%

“…Other sources providing RUCAM based HILI cases include the Chinese Academy of Medical Sciences in Beijing [ 195 ], School of Chinese Materia Medica in Beijing [ 199 , 202 ], Competence Centre for Complementary Medicine and Naturopathy in Munich [ 211 ], Biomedical Research and Innovation Platform South African Medical Research Council in Tygerberg [ 239 ], United States Pharmacopeia in Rockville [ 254 ], and Center of Pharmacovigilance of Florence [ 218 ].…”

Section: Worldwide Publications Of Hili Cases Assessed For Causalimentioning

confidence: 99%

Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993–Mid 2020: A Comprehensive Analysis

Teschke

Danan²

2020

Medicines

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Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusion: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions.

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Development and validation of a sensitive liquid chromatography‐tandem mass spectrometry method for the assay of 12 substances in rat plasma and its application to rat pharmacokinetics of Epimedium and Psoraleae Fructus herb pair after oral administration

Wang,

Yin,

Liu

et al. 2024

J of Separation Science

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Epimedium (EM) and Psoraleae Fructus (PF) are a traditional herb combination often used as a fixed form to treat osteoporosis disease in the clinic. However, the intricate interactions of this pair remain unknown. In our study, we undertook a comprehensive examination of their compatibility behaviors. Concurrently, a precise and sensitive quantitation method was successfully developed and validated using liquid chromatography‐tandem mass spectrometry for the determination of 12 components. This method was applied in analyzing herbal extracts and biological samples (both in the portal vein and systemic plasma), which was also used to study the pharmacokinetics of the herb pair. The results indicated that the combination of EM and PF enhanced the dissolution of chemical components from PF in extracts, but it had a negligible influence on the contents of the components from EM. On the contrary, the in vivo exposure of the lowly exposed EM flavonoids significantly increased following the combination of EM and PF, whereas the highly exposed psoralen and isopsoralen were greatly reduced. These interactions might be crucial for the synergy and toxicity reduction of the herbal pair in disease treatment, which pave the way for further exploration into the clinical application and pharmacological mechanisms of EM and PF.

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

Cited by 47 publications

References 51 publications

Icarisid I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

Icarisid I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity

Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993–Mid 2020: A Comprehensive Analysis

Development and validation of a sensitive liquid chromatography‐tandem mass spectrometry method for the assay of 12 substances in rat plasma and its application to rat pharmacokinetics of Epimedium and Psoraleae Fructus herb pair after oral administration

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