Molecular mechanisms involved in drug-induced liver injury caused by urate-lowering Chinese herbs: A network pharmacology study and biology experiments

Abstract

As an important part of the comprehensive treatment methods, the urate-lowering Chinese herbs could provide favorable clinical effects on hyperuricemia in its ability to invigorate spleen and remove dampness. Owing to the long-term duration, it brought up the potential adverse reactions (ADRs) and concerns about the drug-induced liver injury from these herbs. To address this problem, the bioinformatics approaches which combined the network pharmacology, computer simulation and molecular biology experiments were undertaken to elucidate the underlying drug-induced liver injury molecular mechanisms of urate-lowering Chinese herbs. Several electronic databases were searched to identify the potential liver injury compounds in published research. Then, the putative target profile of liver injury was predicted, and the interaction network was constructed based on the links between the compounds, corresponding targets and core pathways. Accordingly, the molecular docking simulation was performed to recognize the representative compounds with hepatotoxicity. Finally, the cell experiments were conducted to investigate the biochemical indicators and expression of the crucial protein that were closely associated with liver injury. In conclusion, the current research revealed that the compounds with potential liver injury including diosgenin, baicalin, saikosaponin D, tetrandrine, rutaecarpine and evodiamine from urate-lowering Chinese herbs, could lead to decline the survival rate of L-02 cell, increase the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) in cell-culture medium, enhance the expression of p-p38/p38, while the p38 inhibitor could achieve the trend of regulating and controlling liver injury. These research findings bring further support to the growing evidence that the mechanism of the liver injury induced by the compounds from urate-lowering Chinese herbs may be associated with the activation of p38α.

Synthesis, biological evaluation and toxicity of novel tetrandrine analogues

“…Thus, formation of quinone methides does not necessarily lead to toxicity in vitro and in vivo . For tetrandrine ( 1 ), other proposed mechanisms might play a more substantial role in toxicity, such as the generation of ROS by CYP2E1 [ 32 ] or the proposed interaction with p38α MAPK, a promotor of inflammatory processes in the liver [ 31 ], or additional effects that remain to be elucidated.…”

“…The molecular mechanism of tetrandrine-induced toxicity has not been entirely elucidated yet. Li and coworkers [ 31 ] hypothesized that an interaction of tetrandrine with p38α MAPK (mitogen-activated protein kinase) led to liver injury, whereas several other studies suggest the involvement of cytochrome P450 (CYP) enzymes in tetrandrine-induced pulmonary [ 26 , 27 ] and hepatic toxicity [ 32 ]. Qi et al.…”

Mechanism of drug-induced liver injury and hepatoprotective effects of natural drugs

“…The levels of ALT, LDH and ALP increased in the cell culture medium. The mechanism of liver injury may be related to the activation of p38α [ 44 ]. In contrast, idiosyncratic hepatotoxicity (idiopathic DILI) is more common in the clinic and includes immune idiopathic liver injury or inflammatory idiopathic liver injury.…”

Research progress on evodiamine, a bioactive alkaloid of Evodiae fructus: Focus on its anti‑cancer activity and bioavailability (Review)

“…It has been reported that the alkaloid-rich extract of Evodiae fructus is likely to cause hepatic injury in mice (31). As a major alkaloid compound contained within Evodiae fructus, hepatotoxicity mediated by EVO is induced by enhancing the activity of aspartate aminotransferase, alanine transaminase, lactate dehydrogenase and alkaline phosphatase (32).…”