Modulation of Glutathione S-Transferase Alpha by Hepatitis B Virus and the Chemopreventive Drug Oltipraz

Jaitovitch-Groisman, Iris; Fotouhi‐Ardakani, Nasser; Schecter, Robyn L.; Woo, Annie; Alaoui‐Jamali, Moulay A.; Batist, Gerald

doi:10.1074/jbc.m003754200

Cited by 28 publications

(12 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such an experiment was not possible using the LipofectAMINE transfection assay because of the very low transfection efficiency in liver cells (Ͻ5-8%). We reported previously that the HBx retroviral vector used in this study is efficient in expressing HBx (19,20). We confirmed the presence of functional HBx by its ability to transactivate AP1 and NF-B elements.…”

Section: Effect Of Hbx On Endogenous Mrna and Protein Expression Levesupporting

confidence: 72%

“…Vesicular stomatitus virus-G pseudotyped retroparticles AP2 and AP2-HBx were collected as described (20) and utilized to transduce target cells. Five g of linear DNA containing either pAP2 or pAP2-HBx were co-transfected in a ratio 50:1 with the Zeocin-resistant plasmid pJ6⍀2bleo (36) using LipofectAMINE according to the recommendations of the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional Regulation of the TFIIH Transcription Repair Components XPB and XPD by the Hepatitis B Virus x Protein in Liver Cells and Transgenic Liver Tissue

Jaitovich-Groisman¹,

Benlimame²,

Slagle³

et al. 2001

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Section: Effect Of Hbx On Endogenous Mrna and Protein Expression Levesupporting

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Transcriptional Regulation of the TFIIH Transcription Repair Components XPB and XPD by the Hepatitis B Virus x Protein in Liver Cells and Transgenic Liver Tissue

Jaitovich-Groisman¹,

Benlimame²,

Slagle³

et al. 2001

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…A series of fragments containing the rat GSTA5 promoter described in a previous report from this lab (Jaitovitch-Groisman et al, 2000) were amplified by polymerase chain reaction (PCR) from rat genomic DNA using primers specific for the rat GSTA5 5Ј-flanking region. The PCR product was digested with XhoI and HindIII and ligated into pGL3-basic vector (Promega, Madison, WI) containing a firefly luciferase reporter gene.…”

Section: Methodsmentioning

confidence: 99%

Oltipraz Is a Bifunctional Inducer Activating Both Phase I and Phase II Drug-Metabolizing Enzymes via the Xenobiotic Responsive Element

Miao

Kandouz

et al. 2003

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Oltipraz, a promising cancer chemopreventive agent, has been recognized as a monofunctional inducer selectively activating phase II carcinogen-detoxifying enzymes via the antioxidant responsive element (ARE). However, we report here that oltipraz also induces rat glutathione S-transferase A5 (GSTA5), a potent phase II detoxifying enzyme, by means of the xenobiotic responsive element (XRE). Although an ARE sequence exists in the 5Ј upstream of the rGSTA5 gene, this cis-acting regulatory element loses its responsiveness to oltipraz treatment because of extensive mutations in its distal-half site. Our data indicate that a XRE sequence, located downstream of the transcription initiation site of the gene, is another oltipraz-responsive element. Electrophoretic mobility shift assay showed that oltipraz steadily induces XRE-aryl hydrocarbon receptor (AhR) binding, which can be blocked specifically by excess XRE oligonucleotides or by AhR antibody. By cloning different XREs into the pGL3-promoter vector, we found that oltipraz can activate XRE enhancers from several phase II drug metabolism enzymes, including rGSTA5, rGSTA2, NAD(P)H:quinone reductase, and it also activates XRE from the phase I metabolism enzyme CYP1A1. Oltipraz's effect on XRE is AhR-dependent and is independent of the presence of active CYP1A1. Reverse transcriptase-polymerase chain reaction experiments revealed that oltipraz induces gene expression of both phase I and II drugmetabolizing enzymes in rat hepatoma cells. Thus, we conclude that, like ARE, the XRE pathway constitutes an important part of the molecular mechanism contributing to oltipraz-induced expression of the phase II metabolism enzymes. Oltipraz is a bifunctional inducer, modulating both phase I and II drugmetabolizing enzymes to enhance carcinogen detoxification.Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] is considered one of the most promising chemopreventive agents based on the results of preclinical studies and preliminary clinical trials (Clapper, 1998;Kensler et al., 1999). Numerous data have demonstrated that oltipraz provides significant protection from tumorigenesis in hepatocellular, mammary, colon, and lung tumor models, and that it induces resistance to many types of carcinogens including aflatoxin B1 (AFB1), a well known hepatocellular carcinogen (Clapper, 1998).It has been shown that oltipraz's chemopreventive effect is caused by the selective induction of phase II drug-metabolizing enzymes and/or the inhibition of some phase I cytochrome P450 enzyme activities (Kensler et al., 1999). As a major molecular mechanism, the induction of the phase II drug metabolism enzymes helps to detoxify various types of carcinogens. It was previously demonstrated that up-regulation of phase II enzymes by oltipraz is caused by the direct activation of the antioxidant-responsive element (ARE), a cisacting regulatory element that is widely present in the 5Ј-flanking regions of many detoxifying genes (Kensler et al., 1999). The ARE was first identified in rat glutathione ...

show abstract

“…Comprehensive mechanistic studies indicate that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferases (GSTs) (Bolton et al, 1993;Kensler, 1997). GST induction also accounts for the cytoprotective effect of oltipraz against toxicantinduced injury (Jaitovitch-Groisman et al, 2000;Nelson et al, 2002). A phase IIa randomized chemoprevention trial of oltipraz in residents of Qidong, China, showed that oltipraz might be clinically active as a chemopreventive agent.…”

Section: Introductionmentioning

confidence: 99%

DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

Lee²,

Kim

et al. 2006

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Comprehensive mechanistic studies suggest that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferase (GST). Previously, we have shown that the activation of CCAAT/enhancer binding protein-␤ (C/EBP␤), promoted by oltipraz, contributes to the transcriptional induction of the GSTA2 gene. Studies also indicated that exposure of animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) with an increase in Nrf2's antioxidant response element (ARE) binding activity. Given the previous reports that C/EBP␤ activation contributes to oltipraz's induction of the GSTA2 gene and that Nrf2 activation by oltipraz was variable depending on the concentrations, this study investigated whether the major oxidized metabolites of oltipraz induce GSTA2 through the activation of C/EBP␤ and/or Nrf2. Immunoblot analysis revealed that M1 Oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiol-3-thione] has been studied as a chemopreventive agent for malignancies, such as liver and colorectal cancer (Rao et al., 1993;Kensler, 1997). Comprehensive mechanistic studies indicate that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferases (GSTs) (Bolton et al., 1993;Kensler, 1997). GST induction also accounts for the cytoprotective effect of oltipraz against toxicantinduced injury (Jaitovitch-Groisman et al., 2000;Nelson et al., 2002). A phase IIa randomized chemoprevention trial of oltipraz in residents of Qidong, China, showed that oltipraz might be clinically active as a chemopreventive agent. In the human studies, oltipraz dosage regimens with higher doses and a long-dosing interval seemed to be more efficacious in preventing cancer, as supported by a significant decline in the levels of aflatoxin-albumin adduct in the individuals receiving a higher dose of oltipraz (500 mg/week) (Jacobson et al., 1997;Jackson and Groopman, 1999;Wang et al., 1999).Exposure of experimental animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) Iida et al., 2004) and enhances Nrf2's antioxidant response element (ARE) binding activity (Pietsch et al., 2003). Diminished expression of phase II enzyme genes by oltipraz in the Nrf2 Ϫ/Ϫ mice supports the role of Nrf2 activation in its cancer chemopreventive effects Ramos-Gomez et al., 2001). Molecular signals activated by oxidative stress stimulate translocation of Nrf2 to the nucleus, where it binds and activates the AREs located in the promoter regions of phase II enzyme genes (Moinova and Mulcahy, 1998;Venugopal and Jaiswal, 1998;Huang et al., 2000).Studies from this laboratory showed that oltipraz at clinically relevant concentrations marginally increased the band intensity of Nrf2 ARE binding and thus weakly enhanced the accumulation of Nrf2 in the nucleus. Our results suggested that GSTA2 induction by oltipraz might be mediated by the activation of other transcriptional Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.doi:10...

show abstract

Modulation of Glutathione S-Transferase Alpha by Hepatitis B Virus and the Chemopreventive Drug Oltipraz

Cited by 28 publications

References 56 publications

Transcriptional Regulation of the TFIIH Transcription Repair Components XPB and XPD by the Hepatitis B Virus x Protein in Liver Cells and Transgenic Liver Tissue

Transcriptional Regulation of the TFIIH Transcription Repair Components XPB and XPD by the Hepatitis B Virus x Protein in Liver Cells and Transgenic Liver Tissue

Oltipraz Is a Bifunctional Inducer Activating Both Phase I and Phase II Drug-Metabolizing Enzymes via the Xenobiotic Responsive Element

DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

Contact Info

Product

Resources

About