Theoretical study of the SNV reaction of trichloroethylene (TCE) and CH3S-as a model for glutathione conjugation of TCE

Trichloroethylene (TCE), a major environmental pollutant, is activated to m utagenic and nephrotoxic intermediates through a glutathione (GSH) conjugat ion pathway. Three product isomers of GSH-TCE conjugation, having potential ly different toxicities, are theoretically possible: cis- or trans-S-(1,2-d ichlorovinyl)glutathione (cis- or trans-1,2-DCVG, respectively) or 2,2-DCVG . This study involved application of ab initio molecular orbital theory to computing potential energy profiles (PEPs) and predicting product outcome o f the reaction of CH3S- with TCE as a model for GSH-TCE conjugation in biol ogical systems. A goal of this study was to determine the extent to which a body of chemical knowledge pertaining to nucleophilic vinylic substitution (SNV) reactions, of which the GSH-TCE conjugation is a representative exam ple, is relevant to this biological conjugation problem. PEPs were computed fur all studied species at the HF/6-31+G* level of theory; electron correl ation effects were estimated at the MP2/6-31SG* and MP4/6-31+G* levels, and the influence of solvation was estimated using the PS-GVB solvation model, Multiple proposed reaction pathways were considered, including conjugation at the C-1 or C-2 site on TCE, by in-plane (sigma) or out-of-plane (pi) ap proach of the nucleophile. Some aspects of the MP2 and HF PEPs were found t o differ significantly. However, on the basis of comparison of activation b arriers, calculations at all levels of theory predict preference for Ca con jugation over C1 conjugation and formation of the trans-1,2-DCVM product ov er the cis-1,2-DCVM product. These predictions are consistent with GSH-TCE conjugation results from in vivo experiments. In contrast, relative product energies appear to be a poor indicator of the product outcome for this sys tem. Hence, theoretical consideration of the reaction chemistry in the vici nity of the site of nucleophilic addition appears to be necessary and suffi cient to predict the outcome of the enzyme-mediated GSH-TCE conjugation.