Theoretical Study of the SNV Reaction of Trichloroethylene (TCE) and CH3S- as a Model for Glutathione Conjugation of TCE
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- 作者：Joong-Youn Shim ; Phillip F. Boone ; and Ann M. Richard
- 刊名：Chemical Research in Toxicology
- 出版年：1999
- 出版时间：April 1999
- 年：1999
- 卷：12
- 期：4
- 页码：308 - 316
- 全文大小：267K
- 年卷期：v.12,no.4(April 1999)
- ISSN：1520-5010
文摘
Trichloroethylene (TCE), a major environmental pollutant, is activated to mutagenic andnephrotoxic intermediates through a glutathione (GSH) conjugation pathway. Three productisomers of GSH-TCE conjugation, having potentially different toxicities, are theoreticallypossible: cis- or trans-S-(1,2-dichlorovinyl)glutathione (cis- or trans-1,2-DCVG, respectively)or 2,2-DCVG. This study involved application of ab initio molecular orbital theory to computingpotential energy profiles (PEPs) and predicting product outcome of the reaction of CH3S- withTCE as a model for GSH-TCE conjugation in biological systems. A goal of this study was todetermine the extent to which a body of chemical knowledge pertaining to nucleophilic vinylicsubstitution (SNV) reactions, of which the GSH-TCE conjugation is a representative example,is relevant to this biological conjugation problem. PEPs were computed for all studied speciesat the HF/6-31+G* level of theory; electron correlation effects were estimated at the MP2/6-31+G* 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, includingconjugation at the C1 or C2 site on TCE, by in-plane (
) or out-of-plane (
) approach of thenucleophile. Some aspects of the MP2 and HF PEPs were found to differ significantly. However,on the basis of comparison of activation barriers, calculations at all levels of theory predictpreference for C2 conjugation over C1 conjugation and formation of the trans-1,2-DCVM productover the cis-1,2-DCVM product. These predictions are consistent with GSH-TCE conjugationresults from in vivo experiments. In contrast, relative product energies appear to be a poorindicator of the product outcome for this system. Hence, theoretical consideration of the reactionchemistry in the vicinity of the site of nucleophilic addition appears to be necessary andsufficient to predict the outcome of the enzyme-mediated GSH-TCE conjugation.
) or out-of-plane () approach of thenucleophile. Some aspects of the MP2 and HF PEPs were found to differ significantly. However,on the basis of comparison of activation barriers, calculations at all levels of theory predictpreference for C2 conjugation over C1 conjugation and formation of the trans-1,2-DCVM productover the cis-1,2-DCVM product. These predictions are consistent with GSH-TCE conjugationresults from in vivo experiments. In contrast, relative product energies appear to be a poorindicator of the product outcome for this system. Hence, theoretical consideration of the reactionchemistry in the vicinity of the site of nucleophilic addition appears to be necessary andsufficient to predict the outcome of the enzyme-mediated GSH-TCE conjugation.