Stereoselective formation of glutathione S-conjugates from halovinylmercapturate sulphoxides

1. The glutathione S-transferase catalysed formation of glutathione S-conjugates from halovinylmercapturate sulphoxides was investigated in rat liver and kidney cytosol, with purified glutathione S-transferases and in rat in vivo. 2. The two diastereomers of the sulphoxides of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine, N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine show different reactivities with glutathione and glutathione S-transferases. Rat liver and kidney cytosol catalyses the formation of a 1:1 mixture of two diastereomers of (E)-N-acetyl-S-(2-glutathione-S-yl-2-chlorovinyl)-L-cysteine sulphoxide from N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine sulphoxide and of (E)-N-acetyl-S-(2-glutathione-S-yl-1,2-dichlorovinyl)-L-cysteine sulphoxide from N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine sulphoxide. In contrast, only one diastereomer of the Z-isomers was formed. 3. N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulphoxide reacted spontaneously with glutathione at high rates, a 1:1 mixture of both diastereomers of N-acetyl-S-(2-glutathione-S-yl-1-chlorovinyl)-L-cysteine sulphoxide was formed. 4. Metabolism of N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine sulfoxide and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide under by alpha-class glutathione S-transferases yielded identical products as observed with the cytosolic enzymes. No reaction was observed in the presence of rat liver mu class glutathione S-transferases or human glutathione S-transferase M1. 5. Formation of these glutathione conjugates was also observed in the bile of rat after i.p. administration of the mercapturic acid sulphoxides. The results obtained show that stereochemical aspects may govern the regioselectivity and substrate specificity in glutathione S-transferase-catalysed reactions.