2. Academic Validation
  3. Psoralidin, a major component of Psoraleae Fructus, induces inflammasome activation and idiosyncratic liver injury

Psoralidin, a major component of Psoraleae Fructus, induces inflammasome activation and idiosyncratic liver injury

  • Int Immunopharmacol. 2021 Mar;92:107352. doi: 10.1016/j.intimp.2020.107352.
Yan Wang 1,  Guang Xu 2,  Zhilei Wang 3,  Ruisheng Li 4,  Xiaoyan Zhan 5,  Hongbin Liu 3,  Qin Qin 2,  Weixia Li 6,  Xiaoyan Wang 6,  Mingliang Zhang 6,  Jinfa Tang 7,  Zhaofang Bai 8,  Xiaohe Xiao 9
Affiliations

Affiliations

  • 1 School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China.
  • 2 China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China.
  • 3 China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
  • 4 Research Center for Clinical and Translational Medicine, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100500, China.
  • 5 China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; Integrative Medical Center, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China.
  • 6 Department of Pharmacy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China.
  • 7 Department of Pharmacy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China. Electronic address: a0519@163.com.
  • 8 China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; Integrative Medical Center, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: baizf2008@hotmail.com.
  • 9 China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China; Integrative Medical Center, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China. Electronic address: pharmacy302@126.com.
PMID: 33422760 DOI: 10.1016/j.intimp.2020.107352
Abstract

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially fatal disease that is unpredictable and independent of the dose of the drug. Increasing evidence suggests that the majority of IDILI cases are immune-mediated, and the aberrant activation of inflammasome plays a vital role in progression. Psoraleae Fructus (PF), a tonic Chinese medicine, has been able to cause IDILI, but the precise mechanism of hepatotoxicity remains unclear. In this study, eight bioactive compounds involved in PF-induced inflammasome activation were investigated. The results demonstrated that psoralidin activated the inflammasomes followed by secreting Caspase-1 and interleukin 1β (IL-1β) in a dose-dependent manner. Interestingly, MCC950, a potent inhibitor of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, could not entirely suppress the psoralidin-induced inflammasome activation. Moreover, psoralidin significantly induced IL-1β maturation and Caspase-1 activation in NLRP3-knockout bone marrow-derived macrophages (BMDMs), suggesting that psoralidin not only activates the NLRP3 inflammasome but also activates other types of inflammasomes. The results also demonstrated that psoralidin activated the inflammasomes by promoting the C-terminal Caspase recruitment domain (ASC) oligomerization, and the production of mitochondrial Reactive Oxygen Species (mtROS) is a decisive factor in psoralidin-induced inflammasome activation. Importantly, in vivo data revealed that psoralidin induced hepatic inflammation, increased aminotransferase activity and increased the production of IL-1β and tumor necrosis factor(TNF-α) in a susceptible mouse model of lipopolysaccharide (LPS)-mediated IDILI. In summary, these results confirmed that psoralidin causes IDILI by inducing inflammasome activation. The study suggests that psoralidin is a possible risk factor and is responsible for PF-induced IDILI.

Keywords

Idiosyncratic drug-induced liver injury; Inflammasomes; Mitochondrial reactive oxygen species; Psoraleae Fructus; Psoralidin.

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