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tive cysteine conjugate â-lyase inhibitor (aminooxy)acetic
acid did not protect against S-(1,2-dichlorovinyl)-L-cys-
teine sulfoxide induced nephrotoxicity in vivo (61), con-
sistent with a role of the sulfoxide as a Michael acceptor,
which in turn may bind to cellular components without
further activation. These findings are in line with our
results, which demonstrated the cytotoxicity of the mer-
capturic acids in rat renal epithelial cells not being
blocked by (aminooxy)acetic acid. This observation sug-
gests that cysteine conjugate â-lyase mediated bioacti-
vation is not involved in the toxicity of the mercapturate
sulfoxides. Also, N-Ac-TCVC-SO and N-Ac-DCVC-SO
were more toxic in rat renal proximal tubular cells than
their corresponding mercapturic acids. Thus, these sul-
foxidation reactions have to be considered as a bioacti-
vation reaction for N-Ac-TCVC and N-Ac-DCVC, since
the formed vinyl sulfoxides are direct acting electrophiles
and Michael acceptors (54, 62), which are capable of
reacting with cellular constituents.
The formation of sulfoxides from mercapturic acids
thus represents a novel biotransformation pathway in the
glutathione dependent metabolism of chlorinated alkenes
in addition to the cleavage of the mercapturates by
acylases to the corresponding cysteine S-conjugates and
further processing by cysteine S-conjugate â-lyase to toxic
intermediates.
Ack n ow led gm en t . The help of Mrs. Ruckdeschel
(Institut fu¨ r Organische Chemie der Universita¨t
1
Wu¨rzburg, FRG) for recording H and 13C NMR spectra
is gratefully acknowledged, as well as that of Mrs. E.
J a¨ger (Institut fu¨r Pharmazie und Lebensmittelchemie
der Universita¨t Wu¨rzburg, FRG) for mass spectrometrical
analysis.
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