Structure-activity relationship for the biotransformation of haloalkenes by rat liver microsomal glutathione transferase 1.
Chem Res Toxicol
; 15(8): 1036-41, 2002 Aug.
Article
in En
| MEDLINE
| ID: mdl-12184787
ABSTRACT
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Microsomes, Liver
/
Glutathione Transferase
/
Hydrocarbons, Chlorinated
Limits:
Animals
Language:
En
Journal:
Chem Res Toxicol
Journal subject:
TOXICOLOGIA
Year:
2002
Document type:
Article
Affiliation country:
United States