Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism. 2016

Xinmiao Yan, and Hong Kang, and Jun Feng, and Yiyan Yang, and Kailin Tang, and Ruixin Zhu, and Li Yang, and Zhengtao Wang, and Zhiwei Cao
School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. 1434316@tongji.edu.cn.

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.

UI MeSH Term Description Entries
D007527 Isoenzymes Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics. Alloenzyme,Allozyme,Isoenzyme,Isozyme,Isozymes,Alloenzymes,Allozymes
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D011763 Pyrrolizidine Alkaloids A group of ALKALOIDS, characterized by a nitrogen-containing necine, occurring mainly in plants of the BORAGINACEAE; COMPOSITAE; and LEGUMINOSAE plant families. They can be activated in the liver by hydrolysis of the ester and desaturation of the necine base to reactive electrophilic pyrrolic CYTOTOXINS. Pyrrolizidine Alkaloid,Senecio Alkaloid,Senecio Alkaloids,Alkaloid, Pyrrolizidine,Alkaloid, Senecio,Alkaloids, Pyrrolizidine,Alkaloids, Senecio
D005978 Glutathione A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides. Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D005979 Glutathione Peroxidase An enzyme catalyzing the oxidation of 2 moles of GLUTATHIONE in the presence of HYDROGEN PEROXIDE to yield oxidized glutathione and water. Cytosolic Glutathione Peroxidase,Glutathione Lipoperoxidase,Selenoglutathione Peroxidase,Glutathione Peroxidase, Cytosolic,Lipoperoxidase, Glutathione,Peroxidase, Glutathione,Peroxidase, Selenoglutathione
D005982 Glutathione Transferase A transferase that catalyzes the addition of aliphatic, aromatic, or heterocyclic FREE RADICALS as well as EPOXIDES and arene oxides to GLUTATHIONE. Addition takes place at the SULFUR. It also catalyzes the reduction of polyol nitrate by glutathione to polyol and nitrite. Glutathione S-Alkyltransferase,Glutathione S-Aryltransferase,Glutathione S-Epoxidetransferase,Ligandins,S-Hydroxyalkyl Glutathione Lyase,Glutathione Organic Nitrate Ester Reductase,Glutathione S-Transferase,Glutathione S-Transferase 3,Glutathione S-Transferase A,Glutathione S-Transferase B,Glutathione S-Transferase C,Glutathione S-Transferase III,Glutathione S-Transferase P,Glutathione Transferase E,Glutathione Transferase mu,Glutathione Transferases,Heme Transfer Protein,Ligandin,Yb-Glutathione-S-Transferase,Glutathione Lyase, S-Hydroxyalkyl,Glutathione S Alkyltransferase,Glutathione S Aryltransferase,Glutathione S Epoxidetransferase,Glutathione S Transferase,Glutathione S Transferase 3,Glutathione S Transferase A,Glutathione S Transferase B,Glutathione S Transferase C,Glutathione S Transferase III,Glutathione S Transferase P,Lyase, S-Hydroxyalkyl Glutathione,P, Glutathione S-Transferase,Protein, Heme Transfer,S Hydroxyalkyl Glutathione Lyase,S-Alkyltransferase, Glutathione,S-Aryltransferase, Glutathione,S-Epoxidetransferase, Glutathione,S-Transferase 3, Glutathione,S-Transferase A, Glutathione,S-Transferase B, Glutathione,S-Transferase C, Glutathione,S-Transferase III, Glutathione,S-Transferase P, Glutathione,S-Transferase, Glutathione,Transfer Protein, Heme,Transferase E, Glutathione,Transferase mu, Glutathione,Transferase, Glutathione,Transferases, Glutathione
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000094765 Glutathione Peroxidase GPX1 One of the most abundant isoenzymes of the glutathione peroxidase family. Located in the cytosol and mitochondria, it catalyzes the reduction of HYDROGEN PEROXIDE to water, functioning to limit the accumulation of hydrogen peroxide and modulating processes that utilize hydrogen peroxide; and also the reduction of other organic hydroperoxides to their corresponding alcohols. GPX1 Glutathione Peroxidase,Glutathione Peroxidase 1,GPX1, Glutathione Peroxidase,Glutathione Peroxidase, GPX1
D060066 Protein Interaction Maps Graphs representing sets of measurable, non-covalent physical contacts with specific PROTEINS in living organisms or in cells. Protein-Protein Interaction Map,Protein-Protein Interaction Network,Protein Interaction Networks,Interaction Map, Protein,Interaction Map, Protein-Protein,Interaction Network, Protein,Interaction Network, Protein-Protein,Map, Protein Interaction,Map, Protein-Protein Interaction,Network, Protein Interaction,Network, Protein-Protein Interaction,Protein Interaction Map,Protein Interaction Network,Protein Protein Interaction Map,Protein Protein Interaction Network,Protein-Protein Interaction Maps,Protein-Protein Interaction Networks
D062105 Molecular Docking Simulation A computer simulation technique that is used to model the interaction between two molecules. Typically the docking simulation measures the interactions of a small molecule or ligand with a part of a larger molecule such as a protein. Molecular Docking,Molecular Docking Simulations,Molecular Docking Analysis,Analysis, Molecular Docking,Docking Analysis, Molecular,Docking Simulation, Molecular,Docking, Molecular,Molecular Docking Analyses,Molecular Dockings,Simulation, Molecular Docking

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