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J Biol Chem, Vol. 275, Issue 5, 3693-3698, February 4, 2000
From the Human immunodeficiency virus (HIV) progressively
depletes GSH content in humans. Although the accumulated evidence
suggests a role of decreased GSH in the pathogenesis of HIV,
significant controversy remains concerning the mechanism of GSH
depletion, especially in regard to envisioning appropriate therapeutic
strategies to help compensate for such decreased antioxidant capacity.
Tat, a transactivator encoded by HIV, is sufficient to cause GSH
depletion in vitro and is implicated in AIDS-associated
Kaposi's sarcoma and B cell lymphoma. In this study, we report a
decrease in GSH biosynthesis with Tat, using HIV-1 Tat transgenic
(Tat+) mice. A significant decline in the total intracellular GSH
content in liver and erythrocytes of Tat+ mice was accompanied by
decreased
Molecular Mechanism of Decreased Glutathione Content in Human
Immunodeficiency Virus Type 1 Tat-transgenic Mice*
,
, Department of Molecular Pharmacology and
Toxicology, University of Southern California School of Pharmacy, Los
Angeles, California 90033, the § Department of Environmental
Health Sciences, School of Public Health, University of Alabama at
Birmingham, Birmingham, Alabama 35294, the ¶ Department of
Biochemistry and Molecular Biology, University of Southern
California/Norris Hospital and Research Institute, Los Angeles,
California 90089, and the Department of Pathology, University of
Southern California School of Medicine,
Los Angeles, California 90089
-glutamylcysteine synthetase regulatory subunit mRNA
and protein content, which resulted in an increased sensitivity of
-glutamylcysteine synthetase to feedback inhibition by GSH. Further
study revealed a significant reduction in the activity of GSH
synthetase in liver of Tat+ mice, which was linearly associated with
their GSH content. Therefore, Tat appears to decrease GSH in
vivo, at least partially, through modulation of GSH biosynthetic enzymes.
*
This work was supported by the Dolores Zohrab Liebmann
Fellowship and National Institutes of Health Grant ES05511.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.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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