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Metabolomics- and systems toxicology-based hepatotoxicity mechanism of Sophorae Tonkinensis Radix et Rhizoma in rats

Affiliation
Innovation Research Institute of Traditional Chinese Medicine ,Shanghai University of Traditional Chinese Medicine ,Shanghai ,China
Yu, Dengxiang;
Affiliation
Innovation Research Institute of Traditional Chinese Medicine ,Shanghai University of Traditional Chinese Medicine ,Shanghai ,China
Shao, Zhen;
Affiliation
Innovation Research Institute of Traditional Chinese Medicine ,Shanghai University of Traditional Chinese Medicine ,Shanghai ,China
Fu, Yuemeng;
Affiliation
Innovation Research Institute of Traditional Chinese Medicine ,Shanghai University of Traditional Chinese Medicine ,Shanghai ,China
Tang, Xiaohang;
Affiliation
Shanghai Skin Disease Hospital ,School of Medicine ,Tongji University ,Shanghai ,China
Chen, Qilong;
Affiliation
Innovation Research Institute of Traditional Chinese Medicine ,Shanghai University of Traditional Chinese Medicine ,Shanghai ,China
Deng, Zhongping

Drug-induced liver injury (DILI) is a major challenge to the development and clinical application of drugs, especially limits the global application of Chinese herbal medicines, because the material basis and mechanisms of some Chinese herbal medicines are not well clear. In this study, a comprehensive method integrating metabolomics and systems toxicology (SysT) was used to investigate how the main substances in Sophorae Tonkinensis Radix et Rhizoma (STRER) influence the metabolic pathways and molecular mechanisms of hepatotoxicity. Through a 28-day continuous oral administration toxicity study combined with serum metabolomics analyses, the aqueous, ethanol-precipitation and dichloromethane extracts of STRER exhibited significant hepatotoxic effects. In addition, 19 differential metabolites with a time-dose-effect relationship were identified in rats. The primary bile acid biosynthesis pathway was significantly altered, which was consistent with the findings of the SysT analysis. Furthermore, through the quantification of bile acids in serum, 16 differential bile acids were identified as being significantly changed; moreover, 21 relevant targets which intersected with the hepatotoxic targets of STRER were identified. Molecular docking was used to confirm the validation of bindings between targets and corresponding compounds, and finally, six important compounds and 14 potential targets were identified to be involved in STRER-induced liver injury in relation to bile acid metabolism.

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License Holder: Copyright © 2022 Yu, Shao, Fu, Tang, Chen and Deng.

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