Nc. Luu et al., Bioactivation mechanisms of haloalkene cysteine S-conjugates modeled by gas-phase, ion-molecule reactions, CHEM RES T, 13(7), 2000, pp. 610-615
Glutathione conjugate formation plays important roles in the detoxification
and bioactivation of xenobiotics. A range of nephrotoxic haloalkenes under
go bioactivation that involves glutathione and cysteine S-conjugate formati
on. The cysteine S-conjugates thus formed may undergo cysteine conjugate be
ta-lyase-catalyzed biotransformation to form cytotoxic thiolates or thiiran
es. In the studies presented here, cysteine conjugate beta-lyase-catalyzed
biotransformations were modeled by anion-induced elimination reactions of S
-(2-bromo-1,1,2-trifluoroethyl)-N-acetyl-cysteine L-cysteine methyl ester,
S-(2-chloro-1,1,2-trifluoroethyl)-N-acetyl-L-cysteine methyl ester, and S-(
2-fluoro-1,1,2-trifluoroethyl)-N-acetyl-L-cysteine methyl eater in the gas
phase. Examination of these processes in the gas phase allowed direct obser
vation of the formation of cysteine S-conjugate-derived thiolates and thiir
anes, whose formation is inferred from condensed-phase results. The cystein
e S-conjugates of these haloethenes exhibit distinctive patterns of mutagen
icity that are thought to be correlated with the nature of the products for
med by their cysteine conjugate beta-lyase-catalyzed biotransformation. In
particular, S-(2-bromo-1,1,2-trifluoroethyl)-L-cysteine is mutagenic, where
as the chloro and fluoro analogues are not. It has been proposed that the m
utagenicity of S-(2-bromo-1,1,2-trifluoroethyl)-L-cysteine is correlated wi
th the greater propensity of the bromine-containing cysteine S-conjugate to
form a thiirane compared with those of the chlorine- or fluorine-containin
g conjugates. The ease of thiirane formation is consistent with the gas-pha
se results presented here, which show that the bromine-containing conjugate
has a greater propensity to form a thiirane on anionic base-induced elimin
ation than the chloro- or fluoro-substituted analogues. The blocked cystein
e S-conjugates were deprotonated by gas-phase ion-molecule reactions with h
ydroxide, methoxide, and ethoxide ions and then allowed to decompose. The m
echanisms for these decompositions are discussed as well as the insights in
to the bioactivation of these cysteine S-conjugates provided by the further
decompositions of thiolate intermediates.