1. Molecular mechanisms involved in drug-induced liver injury caused by urate-lowering Chinese herbs: A network pharmacology study and biology experiments.
- Author
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Li F, Dong YZ, Zhang D, Zhang XM, Lin ZJ, and Zhang B
- Subjects
- Alanine Transaminase genetics, Alanine Transaminase metabolism, Alkaline Phosphatase genetics, Alkaline Phosphatase metabolism, Antimetabolites chemistry, Antimetabolites isolation & purification, Antimetabolites pharmacology, Aspartate Aminotransferases genetics, Aspartate Aminotransferases metabolism, Benzylisoquinolines adverse effects, Benzylisoquinolines chemistry, Benzylisoquinolines isolation & purification, Benzylisoquinolines pharmacology, Cell Line, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Computational Biology methods, Flavonoids adverse effects, Flavonoids chemistry, Flavonoids isolation & purification, Flavonoids pharmacology, Gout Suppressants chemistry, Gout Suppressants isolation & purification, Gout Suppressants pharmacology, Hepatocytes drug effects, Hepatocytes pathology, Humans, Hyperuricemia drug therapy, Hyperuricemia physiopathology, Indole Alkaloids adverse effects, Indole Alkaloids chemistry, Indole Alkaloids isolation & purification, Indole Alkaloids pharmacology, L-Lactate Dehydrogenase genetics, L-Lactate Dehydrogenase metabolism, Liver drug effects, Liver pathology, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Mitogen-Activated Protein Kinase 14 genetics, Mitogen-Activated Protein Kinase 14 metabolism, Molecular Docking Simulation, Protein Binding, Quinazolines adverse effects, Quinazolines chemistry, Quinazolines isolation & purification, Quinazolines pharmacology, Saponins adverse effects, Saponins chemistry, Saponins isolation & purification, Saponins pharmacology, Uric Acid antagonists & inhibitors, Uric Acid chemistry, Uric Acid metabolism, Antimetabolites adverse effects, Drugs, Chinese Herbal chemistry, Gene Expression Regulation drug effects, Gout Suppressants adverse effects, Mitogen-Activated Protein Kinase 14 chemistry
- 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., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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