title: Computational and experimental studies on the distribution of addition and substitution products of the microsomal glutathione transferase 1-catalyzed conjugation of glutathione with fluoroalkenes.
abstract: The glutathione transferase-catalyzed reaction of glutathione with haloalkenes results in the formation of addition or substitution products or both. Glutathione conjugates of haloalkenes may be metabolized and excreted at different rates, may follow different metabolic pathways, and may exhibit different toxicities. Microsomal glutathione transferase 1 (MGST1)-catalyzed conjugation 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 of the MGST1-catalyzed reaction of glutathione with haloalkenes. An ab initio computational study 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 and substitution products that resulted from the MGST1-catalyzed reaction of glutathione with these fluoroalkenes. The results show that this computational model accurately predicted the distribution of the addition and substitution products that result from the MGST1-catalyzed reaction of glutathione with these fluoroalkenes.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, 601 Elmwood Avenue, Box 711, Rochester, New York 14642, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Jolivette
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D002384:Catalysis; D005978:Glutathione / Q000737:chemistry*; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008958:Models, Molecular; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000475:Alkenes; D006845:Hydrocarbons, Fluorinated; D005982:Glutathione Transferase; D005978:Glutathione