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Originally published In Press as doi:10.1074/jbc.M003754200 on August 8, 2000

J. Biol. Chem., Vol. 275, Issue 43, 33395-33403, October 27, 2000
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Modulation of Glutathione S-Transferase Alpha by Hepatitis B Virus and the Chemopreventive Drug Oltipraz*

Iris Jaitovitch-GroismanDagger , Nasser Fotouhi-ArdakaniDagger , Robyn L. Schecter, Annie Woo, Moulay A. Alaoui-Jamali, and Gerald Batist§

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-kappa 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.

Dagger 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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