Structure-activity relationship for the biotransformation of haloalkenes by rat liver microsomal glutathione transferase 1.
Many haloalkenes are nephrotoxic in rodents, and experimental evidence supports a glutathione-dependent bioactivation pathway that leads to nephrotoxicity or nephrocarcinogenicity, or both. The reaction of glutathione with haloalkenes is catalyzed by cytosolic glutathione transferases (cGST) and microsomal glutathione transferase 1 (MGST1). The aim of this study was to develop a computational approach to predict the competency of cGST and MGST1 to catalyze the reaction of glutathione with a range of haloalkenes. The hypothesis tested was that the semiempirically computed energy of the lowest unoccupied molecular orbital (E(LUMO)) of a haloalkene may be used to predict the competency of cGST and MGST1 to catalyze its reaction with glutathione. The MGST1- and cGST-catalyzed reaction of glutathione with nine haloalkenes with E(LUMO) values ranging from -1.14 to 0.38 eV was determined experimentally. The data indicated that the E(LUMO) values for haloalkenes were inversely related to the specific activity of the MGST1-catalyzed reaction but not the cGST-catalyzed reaction. These data also demonstrated that MGST1 catalyzed the reaction of glutathione with haloalkenes with E(LUMO) values equal to or more negative than -0.73 eV and that cGST catalyzed the reaction of glutathione with haloalkenes with E(LUMO) values more negative than -0.06 eV.
Jolivette
Larry J
LJ
Department of Pharmacology and Physiology, University of Rochester, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA.
Anders
M W
MW
D000818:Animals; D001711:Biotransformation; D005982:Glutathione Transferase / Q000378:metabolism*; D006843:Hydrocarbons, Chlorinated / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D006843:Hydrocarbons, Chlorinated; C122107:microsomal glutathione S-transferase-I; D005982:Glutathione Transferase