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J. Biol. Chem., Vol. 275, Issue 43, 33395-33403, October 27, 2000
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From the Lady Davis Institute of the Sir Mortimer B. Davis Jewish
General Hospital, The Center for Translational Research in Cancer,
Department of Medicine, McGill University,
Montreal, Quebec H3T 1E2, Canada
Persistent infection by hepatitis B
virus (HBV) and exposure to chemical carcinogens correlates with the
prevalence of hepatocellular carcinoma in endemic areas. The precise
nature of the interaction between these factors is not known.
Glutathione S-transferases (GST) are responsible for the
cellular metabolism and detoxification of a variety of cytotoxic and
carcinogenic compounds by catalysis of their conjugation with
glutathione. Diminished GST activity could enhance cellular sensitivity
to chemical carcinogens. We have investigated GST isozyme expression in
hepatocellular HepG2 cells and in an HBV-transfected subline. Total GST
activity and selenium-independent glutathione peroxidase activity are
significantly decreased in HBV transfected cells. On immunoblotting,
HBV transfected cells demonstrate a significant decrease in the level
of GST Alpha class. Cytotoxicity assays reveal that the HBV transfected
cells are more sensitive to a wide range of compounds known to be
detoxified by GST Alpha conjugation. Although no significant difference
in protein half-life between the two cell lines was found,
semi-quantitative reverse transcription-polymerase chain
reaction shows a reduced amount of GST Alpha mRNA in the
transfected cells. Because the HBV x protein (HBx) seems to play a role
in HBV transfection, we also demonstrated that expression of the HBx
gene into HepG2 cells decreased the amount of GST Alpha protein.
Transient transfection experiments using both rat and human GST Alpha
(rGSTA5 and hGSTA1) promoters in HepG2 cells show a decreased CAT
activity upon HBx expression, supporting a transcriptional regulation
of both genes by HBx. This effect is independent of HBx interaction
with Sp1. Treatment with oltipraz, an inducer of GST Alpha, partially
overcomes the effect of HBx on both promoters. Promoter deletion
studies indicate that oltipraz works through responsive elements
distinct from AP1 or NF-
Modulation of Glutathione S-Transferase Alpha by
Hepatitis B Virus and the Chemopreventive Drug Oltipraz*
,,
B transcription factors. Thus, HBV infection
alters phase II metabolizing enzymes via different mechanisms than
those modulated by treatment with oltipraz.
*
This work was supported by funds from the National Cancer
Institute of Canada, Medical Research Council of Canada, Cancer Research Society Inc.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.
These authors contributed equally to this work.
§
To whom correspondence should be addressed: McGill Center for
Translational Research in Cancer, Lady Davis Inst., Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine Rd., Montreal,
PQ H3T 1E2, Canada. Tel.: 514-340-7915; Fax: 514-340-7576; E-mail:
gbatist@onc.jgh.mcgill.ca.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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