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Integrated proteomics, biological functional assessments and metabolomics reveal toosendanin induced hepatic energy metabolic disorders.
Chemical Research in Toxicology 2019 March 9
Toosendanin (TSN), a compound from Melia toosendan, exerts severe hepatotoxicity, which restricts its clinical application. However, the mechanism is not clear. Our previous research found that covalent modification of TSN for proteins might be a possible reason using human liver microsome, and the glycolytic enzymes, triosephosphate isomerase 1 (TPIS) and α-enolase (ENOA), were responsible for the hepatotoxicity. In this study, we tried to prove them in cell and animal models by integration of proteomics, metabolomics and biological methods. Proteomics analysis in rats showed that TPIS and ENOA were covalently modified by TSN reactive metabolites (RMs). The biological functional assessments exhibited that the modifications inhibited the activity of TPIS and induced the activity of ENOA, respectively, in vitro and in vivo, followed by the increase of cellular methylglyoxal (MG), advanced glycation end products (AGEs) and reactive oxygen species (ROS)/superoxide, the induction of mitochondrial dysfunction, which further inhibited oxidative phosphorylation and stimulated glycolysis. Furthermore, metabolomics demonstrated the decrease of metabolites in tricarboxylic acid cycle, fatty acid β-oxidation and amino acid metabolism, i.e. TSN induced hepatocyte energy metabolism disorder. In conclusion, these data suggest novel mechanistic insights into TSN induced liver injury on the upstream level and provide valuable proteins and energy metabolic targets for diagnosis and therapy in clinic.
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