Computational and Experimental Studies on the Distribution of Addition and Substitution Products of the Microsomal Glutathione Transferase 1-Catalyzed Conjugation of Glutathione with Fluoroalkenes

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• 作者：Larry J. Jolivette and M. W. Anders
• 刊名：Chemical Research in Toxicology
• 出版年：2003
• 出版时间：February 2003
• 年：2003
• 卷：16
• 期：2
• 页码：137 - 144
• 全文大小：130K
• 年卷期：v.16,no.2(February 2003)
• ISSN：1520-5010

文摘

The glutathione transferase-catalyzed reaction of glutathione with haloalkenes results inthe formation of addition or substitution products or both. Glutathione conjugates of haloalkenesmay be metabolized and excreted at different rates, may follow different metabolic pathways,and may exhibit different toxicities. Microsomal glutathione transferase 1 (MGST1)-catalyzedconjugation of chlorotrifluoroethene, hexafluoropropene, and 2-(fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene results in differing proportions of addition and substitution products.The aim of the present study was to develop a computational model to predict the outcome ofthe MGST1-catalyzed reaction of glutathione with haloalkenes. An ab initio computationalstudy of the reaction of ethanethiolate, a surrogate for glutathione, with the chlorotrifluoroethene, hexafluoropropene, and 2-(fluoromethoxy)-1,1,3,3,3-pentafluoro-1-propene was conducted. An empirical study was also conducted to quantify the distribution of addition andsubstitution products that resulted from the MGST1-catalyzed reaction of glutathione withthese fluoroalkenes. The results show that this computational model accurately predicted thedistribution of the addition and substitution products that result from the MGST1-catalyzedreaction of glutathione with these fluoroalkenes.