title: Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism.
abstract: Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. 1434316@tongji.edu.cn.
authors.forename: Xinmiao
authors.initials: X
authors.lastname: Yan
authors.affiliation: School of Biomedical Informatics, University of Texas Health Science Center, Houston, TX 77030, USA. kangh0607@gmail.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Kang
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. qilefeng525@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. 1410775@tongji.edu.cn.
authors.forename: Yiyan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. kltang@tongji.edu.cn.
authors.forename: Kailin
authors.initials: K
authors.lastname: Tang
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. rxzhu@tongji.edu.cn.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Zhu
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. yl7@shutcm.edu.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. ztwang@shutcm.edu.cn.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. zwcao@tongji.edu.cn.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Cao
mesh_terms: D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D062105:Molecular Docking Simulation; D060066:Protein Interaction Maps / Q000187:drug effects; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D007527:Isoenzymes; D011763:Pyrrolizidine Alkaloids; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; D005978:Glutathione; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human
keywords: Pyrrolizidine Alkaloids; glutathion metabolism; hepatotoxicity mechanism; reverse docking