Different Toxic Effects of Racemate, Enantiomers, and Metabolite of Malathion on HepG2 Cells Using High-Performance Liquid Chromatography-Quadrupole-Time-of-Flight-Based Metabolomics

Commercial malathion is a racemic mixture that contains two enantiomers, and malathion has adverse effects on mammals. However, whether these two enantiomers have different effects on animals remains unclear. In this study, we tested the effect of racemate, enantiomers, and metabolite of malathion on the metabolomics profile of HepG2 cells. HepG2 cells showed distinct metabolic profiles when treated with rac-malathion, malaoxon, R-(+)-malathion, and S-(-)-malathion, and these differences were attributed to pathways in amino acid metabolism, oxidative stress, and inflammatory response. In addition, malathion treatment caused changes in amino acid levels, antioxidant activity, and expression of inflammatory genes in HepG2 cells. S-(-)-Malathion exhibited stronger metabolic perturbation than its enantiomer and racemate, consistent with the high level of cytotoxicity of S-(-)malathion. R-(+)-Malathion treatment caused significant oxidative stress in HepG2 cells but induced a weaker disturbance in the amino acid metabolism and a pro-inflammatory response compared to S-(-)-malathion and rac-malathion. Malaoxon caused more significant perturbation on antioxidase and a stronger antiapoptosis effect than its parent malathion. Our results provide insight into the risk assessment of malathion enantiomers and metabolites. We also demonstrate that a metabolomics approach can identify the discrepancy of the toxic effects and underlying mechanisms for enantiomers and metabolites of chiral pesticides.