Disease relevance of AIDS-051946

• When these three constructs were compared in Hep G2 (human) and Hepa 1c1c7 (murine) hepatoma cells, the wild-type sequence was highly activated by diverse inducers, including tert-butylhydroquinone, Michael reaction acceptors, 1,2-dithiole-3-thione, sulforaphane,2,3-dimercapto-1-propanol, HgCl2, sodium arsenite, and phenylarsine oxide [1].
• Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], a substituted 1,2-dithiole-3-thione, protects against the acute and chronic toxicities of many xenobiotics and prevents chemically induced carcinogenicity in several target organs of rodents [2].
• 3H-1,2-dithiole-3-thione targets nuclear factor kappaB to block expression of inducible nitric-oxide synthase, prevents hypotension, and improves survival in endotoxemic rats [3].
• Incubation of human neuroblastoma SH-SY5Y cells with the unique chemoprotectant, 3H-1,2-dithiole-3-thione (D3T), led to a significant elevation of cellular GSH in a concentration-dependent fashion [4].
• We showed that 1,2-dithiole-3-thione (D3T) can increase the level of DT-diaphorase activity and the cytotoxic activity of bioreductive agents in mouse lymphoma cells without increasing these activities in normal mouse marrow cells [5].

High impact information on AIDS-051946

• We have investigated the effect of the potent enzyme inducer and anticarcinogen 3H-1,2-dithiole-3-thione (D3T) on the fate of Nrf2 in murine keratinocytes [6].
• D3T also led to nrf2-dependent repression of 31 genes at 24 h; principally genes related to cholesterol/lipid biosynthesis [7].
• At the highest dose of D3T (0.3 mmol/kg), protein levels of GSTA5 and AFAR were induced by 7- and 27-fold, respectively [8].
• Dietary administration of either 5,6-benzoflavone, 1,2-dithiole-3-thione or oltipraz did not affect the frequency of smoke-induced apoptosis, whereas phenethyl isothiocyanate produced a further significant enhancement [9].
• Treatment of rats with the cancer chemopreventive agent 1,2-dithiole-3-thione (D3T) resulted in a significant increase in hepatic heme oxygenase (HO) activity, which corresponded to increased protein levels of HO-1 [10].

Chemical compound and disease context of AIDS-051946

• Studies with 1,2-dithiole-3-thione as a chemoprotector of hydroquinone-induced toxicity to DBA/2-derived bone marrow stromal cells [11].
• Here, we show that pretreatment of F344 rats with the cancer chemoprotective agent 3H-1,2-dithiole-3-thione (D3T) blocks lipopolysaccharide (LPS)-mediated induction of hepatic iNOS and significantly reduces the associated serum levels of NO metabolites and enzyme markers of toxicity provoked by treatment with LPS [3].

Biological context of AIDS-051946

• Upregulation of the antioxidants and phase 2 enzymes by D3T in Nrf2(+/+) stromal cells resulted in increased resistance to the above oxidant- and electrophile-induced cytotoxicity, whereas D3T treatment of Nrf2(-/-) cells only provided a marginal cytoprotection [12].
• In order to identify additional novel inducible detoxification response genes, a cDNA library was prepared from liver of rats treated with 1,2-dithiole-3-thione (D3T) and was screened by a differential hybridization method [13].
• Thus, protective actions of D3T against the cytotoxic and carcinogenic consequences of chemicals that exert electrophilic or oxidative stresses may be mediated, in part, by the induction of HO-1, FL and FH [10].
• Upregulation of antioxidants and phase 2 enzymes by D3T in Nrf2+/+ cardiac fibroblasts resulted in a dramatically increased resistance to the above species-induced cytotoxicity [14].
• MATERIALS AND METHODS: In the present study, 3H-1,2-dithiole-3-thione (D3T) was used as a potent model inducer whose effects on gene expression and chemopreventive efficacy have been extensively characterized in the rat [15].

Anatomical context of AIDS-051946

• Incubation of Nrf2(+/+) stromal cells with 3H-1,2-dithiole-3-thione (D3T) led to a significant induction of various antioxidants and phase 2 enzymes [12].
• The content of GSH transferase (GST) subunits 1a, 1b, 2, 3, 4, 6, 7, 8, 10 and 11 in the soluble fraction of liver, kidney, small intestine, stomach and lung of control and D3T-fed animals was determined [16].
• In accord with the protective effects against tumorigenesis, 4- to 6-fold increases in the specific activities of aflatoxin-glutathione conjugation were observed in cytosols prepared from livers of animals fed 1,2-dithiole-3-thione [17].
• Factors influencing the induction of DT-diaphorase activity by 1,2-dithiole-3-thione in human tumor cell lines [18].
• In this study, using rat aortic smooth muscle A10 cells as an in vitro system, we have studied the induction of cellular antioxidants by the unique chemoprotector, 3H-1,2-dithiole-3-thione [corrected] (D3T) and the protective effects of the D3T-induced cellular antioxidants against oxidative cell injury [19].

Associations of AIDS-051946 with other chemical compounds

• Such studies revealed that unsubstituted 1,2-dithiole-3-thione was more effective than oltipraz at inhibiting aflatoxin-DNA adduct formation in vivo and at inducing electrophile detoxication enzymes in cell culture [17].
• Upregulation of endogenous glutathione system by 3H-1,2-dithiole-3-thione in pancreatic RINm5F beta-cells as a novel strategy for protecting against oxidative beta-cell injury [20].
• Likewise, 5,6-benzoflavone, indole-3-carbinol, 1,2-dithiole-3-thione and oltipraz failed to modulate apoptosis in the respiratory tract of ECS-exposed rats [21].
• Effects of 3H-1,2-dithiole-3-thione, 1,4-phenylenebis(methylene)selenocyanate, and selenium-enriched yeast individually and in combination on benzo[a]pyrene-induced mutagenesis in oral tissue and esophagus in lacZ mice [22].
• The study was designed to investigate the effects of phenobarbital (PB), 3-methylcholanthrene (3-MC), and oltipraz (OPZ), a synthetic derivative of 1,2-dithiole-3-thione, on the levels of cytochrome P450 1A1/2 and gluthathione transferase (GST) mRNAs in both fresh and cryopreserved human, monkey, and dog hepatocytes in primary culture [23].

Gene context of AIDS-051946

• Only GR, GST, and NQO1 in mouse liver were induced by the D3T treatment [24].
• Transcript levels of 292 genes were elevated in wild-type mice 24 h after treatment with D3T; 79% of these genes were induced in wild-type, but not nrf2-deficient mice [7].
• We showed that 1,2-dithiole-3-thione can selectively increase DT-diaphorase activity in human and murine tumors, and that this enhanced the antitumor activity of bioreductive antitumor agents [25].
• No significant induction of cardiac GSH and GPx was observed with the above D3T treatment [24].
• Treatment with 1,2-dithiole-3-thione at the lowest dose (0.001%) reduced by greater than 80% the volume of liver occupied by GGT or GST-P foci; higher dietary concentrations provided greater than 98% reductions in the volume per cent of these markers for presumptive preneoplastic lesions [17].

Analytical, diagnostic and therapeutic context of AIDS-051946

• D3T, the most potent dithiolethione of this series, was examined by microarray analysis for induction of hepatic genes at an intermediate chemopreventive dose (0.1 mmol/kg) [8].
• Activation of the Nrf2 pathway by oral administration of the Nrf2 inducer 3H-1,2-dithiole-3-thione (D3T) to wild-type mice produced partial protection against MPTP-induced neurotoxicity [26].

References