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J. Biol. Chem., Vol. 275, Issue 34, 26556-26565, August 25, 2000
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From the Department of Pharmacology, Case Western Reserve
University, School of Medicine, Cleveland, Ohio 44106-4965
Oxidative stress broadly impacts cells,
initiating regulatory pathways as well as apoptosis and necrosis. A key
molecular event is protein S-glutathionylation, and
thioltransferase (glutaredoxin) is a specific and efficient catalyst of
protein-SSG reduction. In this study 30-min exposure of H9 and Jurkat
cells to cadmium inhibited intracellular protein-SSG reduction, and
this correlated with inhibition of the thioltransferase system,
consistent with thioltransferase being the primary intracellular
catalyst of deglutathionylation. The thioredoxin system contributed
very little to total deglutathionylase activity. Thioltransferase and
GSSG reductase in situ displayed similar dose-response
curves (50% inhibition near 10 µM cadmium in
extracellular buffer). Acute cadmium exposure also initiated apoptosis,
with H9 cells being more sensitive than Jurkat. Moreover, transfection
with antisense thioltransferase cDNA was incompatible with cell
survival. Collectively, these data suggest that thioltransferase has a
vital role in sulfhydryl homeostasis and cell survival. In separate
experiments, cadmium inhibited the isolated component enzymes of the
thioltransferase and thioredoxin systems, consistent with the vicinal
dithiol nature of their active sites: thioltransferase (IC50
Acute Cadmium Exposure Inactivates Thioltransferase
(Glutaredoxin), Inhibits Intracellular Reduction of
Protein-glutathionyl-mixed Disulfides, and Initiates Apoptosis*
,
1 µM), GSSG reductase
(IC50 1 µM), thioredoxin
(IC50 8 µM), thioredoxin reductase
(IC50 0.2 µM). Disruption of the vicinal
dithiol on thioltransferase (via oxidation to C22-SS-C25; or C25S
mutation) protected against cadmium, consistent with a dithiol
chelation mechanism of inactivation.
*
This research was partially funded by Grant A1-36219 from
the Center for Aids Research, National Institutes of Health (to J. J. M.), by National Institute on Aging program project Grant AG15885 (to J. J. M.), and by a Veterans Administration Merit Review
grant (to J. J. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
This study was conducted by Carol A. Chrestensen in partial
fulfillment of the requirements for the Ph.D. degree, Case Western Reserve University, Department of Pharmacology.
Presented in part at Experimental Biology '99, Washington, DC (FASEB J. 13, A155).
§ To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4965. Tel.: 216-368-3383; Fax: 216-368-3395; E-mail: jjm5@ po.cwru.edu.Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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