Abstract
The stereochemistry of the metabolism of vic-dihaloalkanes to alkenes has been studied. This glutathione-dependent biotransformation may occur by two mechanism. The first mechanism involves the nucleophilic attack of glutathione on the substrate resulting in S-(beta-haloalkyl)glutathione formation; subsequent attack of a second thiol on the sulfur atom of the conjugate yields glutathione disulfide, ethylene, and halide ion. Alternatively, glutathione may abstract a halide ion from the substrate and form ethylene, halide ion, and glutathione sulfenyl halide. These pathways were distinguished by determining the stereoisomeric alkenes formed in the metabolism of meso- and racemic 2,3-dibromobutane, erythro- and threo-2-bromo-3-chlorobutane, and meso-1,2-dideutero-1,2-dichloroethane. The stereochemical configurations of the 2-butenes and 1,2-dideuteroethylene were determined by gas chromatography and by Fourier-transform infrared spectroscopy, respectively. When incubated with glutathione and rat liver cytosol, meso- and racemic 2,3-dibromogutane were converted exclusively to (E)- and (Z)-2-butene, respectively. On the other hand, erytho- and threo-2-bromo-3-chlorobutane were converted to a mixture of (E)- and (Z)-2-butene. meso-1,2-Dideutero-1,2-dichloroethane was converted exclusively to (Z)-1,2-dideuteroethylene. These results suggest that the 2,3-dibromobutanes are metabolized to 2-butenes by a direct E2 elimination, whereas 2-bromo-3-chlorobutanes undergo metabolism to 2-butenes by both an E2 elimination and a substitution-elimination sequence. However, 1,2-dihaloethane metabolism to ethylene proceeds only by the substitution-elimination mechanism; this result is consisent with the formation of ethylene-S-glutathionylepisulfonium ion, a possible reactive species involved in 1,2-dihaloethane mutagenicity.
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|