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.

Keywords: CYP450s; hepatotoxicity; immunity; oxidative stress; triptolide.

FIGURE 1

Schematic diagram of molecular pathogenesis of TP-induced hepatotoxicity. This figure shows that TP-induced hepatotoxicity is mainly related to CYP450s, P-gp, oxidative stress, excessive autophagy, apoptosis, metabolic disorders, immunity, and the gut microbiota. ↑: upregulation; ↓: downregulation; ┬: inhibition.

FIGURE 2

Hypothesis of molecular pathogenesis of TP-induced hepatotoxicity. CYP450 enzymes are involved in TP metabolism and P-gp is involved in TP transport. Some factors such as the continuous use of TP, combined with drugs affecting CYP450s and P-gp, antibiotic abuse, circadian rhythm, and sex differences, should affect the level of TP in the liver. TP itself is hepatotoxic and direct liver toxicity due to excessive exposure to TP, such as oxidative stress, excessive autophagy, apoptosis, metabolic disorders, etc. Cell damage caused by direct hepatotoxicity releases danger signals, such as DAMPs, which can activate the innate and adaptive immune systems, and then a large number of pro-inflammatory factors will be released. The inflammatory response further aggravates liver injury by promoting cell death, inducing excessive autophagy and metabolic disorders, etc. In addition, the imbalance of hepatic immune homeostasis caused by changes in immune cells makes the liver sensitive to external factors, such as LPS, then aggravates hepatotoxicity. Furthermore, gut microbiota mediates the hepatotoxicity of TP by affecting TP in vivo exposure, metabolic homeostasis, and immunity. ↓: downregulation of CYP450s and p-gp; ↑: abnormal increase TP exposure.