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Insights into Protein–Ligand Interactions: Mechanisms, Models, and Methods
Open AccessArticle

Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
School of Biomedical Informatics, University of Texas Health Science Center, Houston, TX 77030, USA
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
Author to whom correspondence should be addressed.
Academic Editor: Christo Z. Christov
Int. J. Mol. Sci. 2016, 17(3), 318;
Received: 30 December 2015 / Revised: 19 February 2016 / Accepted: 24 February 2016 / Published: 7 March 2016
(This article belongs to the Collection Proteins and Protein-Ligand Interactions)
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. View Full-Text
Keywords: Pyrrolizidine Alkaloids; hepatotoxicity mechanism; glutathion metabolism; reverse docking Pyrrolizidine Alkaloids; hepatotoxicity mechanism; glutathion metabolism; reverse docking
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Yan, X.; Kang, H.; Feng, J.; Yang, Y.; Tang, K.; Zhu, R.; Yang, L.; Wang, Z.; Cao, Z. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism. Int. J. Mol. Sci. 2016, 17, 318.

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