Network Pharmacology Combined with Metabolomics Approach to Investigate the Toxicity Mechanism of Paclobutrazol

作者：Kexin Yue, Zhiqiang Liu, Zhiqiang Liu, Zifeng Pi, Hanlin Li, Ying‐Ping Wang, Fengrui Song, Zhongying Liu, Zhongying Liu · 发表于：Chemical Research in Toxicology · 年份：2022 · DOI：10.1021/acs.chemrestox.1c00404 · 被引用次数：15 · 研究领域：Phytochemical Studies and Bioactivities、Chromatography in Natural Products、Plant chemical constituents analysis

Paclobutrazol (PBZ) is a commonly used plant growth regulator (PGR) with good antibacterial activity. It has widespread applications in agricultural production. However, there is limited research reported on the potential risks of human health resulting from PBZ residues. In this study, using Sprague-Dawley rats, we carried out a systematic study on the hepatotoxicity and nephrotoxicity of PBZ in different doses (0.2, 0.5, and 1.0 g/kg). The metabolic profiles and network pharmacology were combined to construct a PBZ-endogenous substances-gene-hepatorenal diseases network to elucidate the underlying mechanism of PBZ's hepatorenal toxicity. At first, metabolomics analysis was done to investigate the metabolites and the related metabolic pathways associated with PBZ. Secondly, the network pharmacology approach was used in further exploration of the toxic targets. Additionally, molecular docking was carried out to investigate the interactions between PBZ and potential targets. The results indicated that PBZ showed obvious toxicity towards the liver and kidney of rats. The metabolomics analysis showed that PBZ mainly affected 4 metabolic pathways, including tryptophan metabolism, arachidonic acid metabolism, linoleic acid metabolism, and purine metabolism. Network pharmacology and molecular docking revealed that CYP1A2, CYP2A6, CYP2E1, MAOA, PLA2G2A, PTGS1, and XDH were critical targets for PBZ hepatorenal toxicity. This preliminary study revealed PBZ's hepatorenal toxicity and p...