The molecular pathogenesis of triptolide-induced hepatotoxicity

Abstract

Triptolide (TP) is the major pharmacologically active ingredient and toxic component of Tripterygium wilfordii Hook. f. However, its clinical potential is limited by a narrow therapeutic window and multiple organ toxicity, especially hepatotoxicity. Furthermore, TP-induced hepatotoxicity shows significant inter-individual variability. Over the past few decades, research has been devoted to the study of TP-induced hepatotoxicity and its mechanism. In this review, we summarized the mechanism of TP-induced hepatotoxicity. Studies have demonstrated that TP-induced hepatotoxicity is associated with CYP450s, P-glycoprotein (P-gp), oxidative stress, excessive autophagy, apoptosis, metabolic disorders, immunity, and the gut microbiota. These new findings provide a comprehensive understanding of TP-induced hepatotoxicity and detoxification.

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

“…56 Previous studies have found that triptolide leads to hepatic oxidative stress via CYP2E1 and Nrf2. 13 Our results showed that hepatic oxidative stress increased in WT mice after triptolide administration, whereas the livers of CXCR3deficient mice did not exhibit oxidative stress, suggesting that CXCR3 was involved in triptolide-induced CLI through regulation of hepatic oxidative stress. Research has revealed that Egr-1 upregulation and AKT phosphorylation are the results of CXCR3 activation and result in ROS generation.…”

“…Oxidative stress stimulates upregulation of the redox-sensitive transcription factors such as NF-κB, AP-1, and Egr-1 expression and increases cellular kinase transduction and phosphorylation of phosphatases, such as AKT . Previous studies have found that triptolide leads to hepatic oxidative stress via CYP2E1 and Nrf2 . Our results showed that hepatic oxidative stress increased in WT mice after triptolide administration, whereas the livers of CXCR3-deficient mice did not exhibit oxidative stress, suggesting that CXCR3 was involved in triptolide-induced CLI through regulation of hepatic oxidative stress.…”

“…However, hepatotoxicity limits its clinical application and development. Similar to ANIT, research has shown that triptolide-induced hepatotoxicity is associated with abnormal BA metabolism, inflammation, oxidative stress, and apoptosis . CXCL10 and CXCR4 are the potential pharmacological targets of triptolide.…”

“…Similar to ANIT, research has shown that triptolide-induced hepatotoxicity is associated with abnormal BA metabolism, inflammation, oxidative stress, and apoptosis. 13 CXCL10 14 and CXCR4 15 are the potential pharmacological targets of triptolide. Due to its narrow therapeutic window, the pharmacological target is often the toxicological target.…”

Network pharmacology and experiment validation investigate the potential mechanism of triptolide in oral squamous cell carcinoma

“…Triptolide shows considerable potential for clinical application in the treatment of many diseases, with various effects including anti-inflammatory, anti-rheumatic, immunosuppressive and anticancer effects (Gao et al, 2021). However, its narrow therapeutic window, poor solubility and low bioavailability, multiple organ toxicity, especially hepatoxicity, limit its clinical applications ( Noel et al, 2019 ; Hu et al, 2022 ). The cell growth of oral cancer and HNSCC can be inhibited, which is related to a dose-dependent apoptosis induced by triptolide and its derivatives ( Chen et al, 2009 ; Caicedo-Granados et al, 2014 ).…”