Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that the antiestrogens tamoxifen and raloxifene may protect against breast cancer, presumably because of a blockade of estrogen receptor (ER)-mediated transcription. Another possible explanation is that antiestrogen-liganded ER transcriptionally induces genes that are protective against cancer. We previously reported that antiestrogen-liganded ERbeta transcriptionally activates the major detoxifying enzyme quinone reductase (QR) [NAD(P)H:quinone oxidoreductase]. It has been established that metabolites of estrogen, termed catecholestrogens, can form DNA adducts and cause oxidative DNA damage. We hypothesize that QR inhibits estrogen-induced DNA damage by detoxification of reactive catecholestrogens. We report here that physiological concentrations of 17beta-estradiol cause oxidative DNA damage, as measured by levels of 8- hydroxydeoxyguanine, in ER-positive MCF7 breast cancer cells, MDA-MB-231 breast cancer cells (ERalpha negative/ERbeta positive) and nontumorigenic MCF10A breast epithelial cells (very low ER), which is dependent on estrogen metabolism. Estrogen-induced 8-hydroxydeoxyguanine was inversely correlated to QR and ERbeta levels and was followed by downstream induction of the DNA repair enzyme XPA. Trans-hydroxytamoxifen, raloxifene, and the pure antiestrogen ICI-182,780 protected against estradiol-mediated damage in breast cancer cells containing ERbeta. This is most likely due to the ability of these antiestrogens to activate expression of QR via ERbeta. We conclude that up-regulation of QR, either by overexpression or induction by tamoxifen, can protect breast cells against oxidative DNA damage caused by estrogen metabolites, representing a possible novel mechanism of tamoxifen prevention against breast cancer.
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PMID:Functional implications of antiestrogen induction of quinone reductase: inhibition of estrogen-induced deoxyribonucleic acid damage. 1271 3

Several compounds originating from cruciferous vegetables and citrus fruits bind to and activate the aryl hydrocarbon receptor (AhR). This receptor plays an important role in the toxicity of the known tumour promoter and potent AhR-agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, vegetables and fruits are generally considered as healthy. Therefore, besides the AhR activation, the natural AhR agonists (NAhRAs) are assumed to show other health-concerning effects. AhR activation induces several cytochrome P450 phase I enzymes involved, e.g. in the bioactivation of carcinogenic polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP), and may as such stimulate DNA adduct formation of those compounds. Therefore, the influence of TCDD, indolo[3,2-b]carbazole (ICZ, an NAhRA originating from cruciferous vegetables) and an NAhRA-containing extract of grapefruit juice (GJE) on BaP-DNA adduct formation in the human Caco-2 cell line was studied. Also, we investigated if different effects of TCDD, ICZ and GJE on adduct formation could be related to the modulation of transcription of biotransformation- and DNA-repair enzymes. Co-exposure to high AhR-activating concentrations of both TCDD and ICZ significantly reduced the amount of BaP-DNA adducts at 0.1 microM BaP, while at higher concentrations of BaP no influence was observed. In contrast, exposure to 0.1 microM BaP combined with GJE showed a significant increase in BaP-DNA adducts, and a significant decrease at 0.3 and 1 microM BaP. These differences could not be related to transcription of the phase I and II enzymes CYP1A1, CYP1B1, NQO1, GSTP1 and UGT1A6 or to transcription of the nucleotide excision repair enzymes ERCC1, XPA, XPC, XPF and XPG. We conclude that ICZ showed a similar effect on BaP-DNA adduct formation than TCDD, while GJE influenced the adduct formation in a different way. The difference in the influence on adduct formation may be due to effects at the level of enzyme activity, rather than gene expression.
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PMID:Influence of TCDD and natural Ah receptor agonists on benzo[a]pyrene-DNA adduct formation in the Caco-2 human colon cell line. 1806 24

Exposure to coal dust has been associated with different chronic diseases and mortality risk. This airborne pollutant is produced during coal mining and transport activities, generating environmental and human toxicity. The aim of this study was to determine the effects of a coal dust methanolic extract on HepG2, a human liver hepatocellular carcinoma cell line. Cells were exposed to 5-100ppm methanolic coal extract for 12h, using DMSO as control. MTT and comet assays were used for the evaluation of cytotoxicity and genotoxicity, respectively. Real time PCR was utilized to quantify relative expression of genes related to oxidative stress, xenobiotic metabolism and DNA damage. Coal extract concentrations did not induce significant changes in HepG2 cell viability after 12h exposure; however, 50 and 100ppm of the coal extract produced a significant increase in genetic damage index with respect to negative control. Compared to vehicle control, mRNA CYP1A1 (up to 163-fold), NQO1 (up to 4.7-fold), and GADD45B (up to 4.7-fold) were up regulated, whereas PRDX1, SOD, CAT, GPX1, XPA, ERCC1 and APEX1 remained unaltered. This expression profile suggests that cells exposed to coal dust extract shows aryl hydrocarbon receptor-mediated alterations, changes in cellular oxidative status, and genotoxic effects. These findings share some similarities with those observed in liver of mice captured near coal mining areas, and add evidence that living around these industrial operations may be negatively impacting the biota and human health.
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PMID:Altered gene expression in HepG2 cells exposed to a methanolic coal dust extract. 2530 35

The contribution of the polymorphic markers of the CHRNA5/A3, CYP2A6, NQO1, XPC, XRCC1, XRCC3, XPD, XPA genes to chronic obstructive pulmonary disease has been assessed. For this purpose, analysis of the gene polymorphisms in case/control groups in Tatar population has been performed. The CHRNA5 (rs16969968) (P = 0.0001, OR = 2.24), CHRNA3 (rs1051730) (P = 0.0001, OR = 2.72) were associated with significantly high risk of chronic obstructive pulmonary disease in recessive model. The disease risk was higher in homozygous carriers of normal allele of CYP2A6 (del) (P = 0.00001, OR = 2.77). Analysis showed an association of the NQO1 (rs1131341), XRCC1 (rs25487), XRCC3 (rs861539), XPC (rs2228001) and XPA (rs1800975) (P = 0.000001, OR = 2.67; P = 0.00001, OR = 0.51; P = 0.0003, OR = 1.76; P = 0.0004, OR = 0.54 and P = 0.007, OR = 0.74) in additive model with chronic obstructive pulmonary disease. We found a significant gene-by-environment interaction of smoking status and XPA (rs1800975) (Pinteract = 0.002); rs16969968, rs1051730 of CHRNA3/5 genes were significantly associated with chronic obstructive pulmonary disease only in smokers. The relationship between the CYP2A6(CYP2A6*4) and smoking pack-years was found (P = 0.0019). The TT genotype of XRCC3 (rs861539) were associated with decreased of lung function parameters: vital capacity % (P = 0.0487), forced vital capacity (%) (P = 0.0032) and forced expiratory volume in 1 s (%) (P = 0.02). The relationship between the XPA (rs1800975) and forced expiratory volume in 1 s (%) (P = 0.0028) was found.
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PMID:[Association of the nicotine and cigarette smoke toxicants metabolic (CHRNA3/5, CYP2A6, NQO1) and DNA repair genes (XRCC1, XRCC3, XPC, XPA) with chronic obstructive pulmonary disease]. 2584 34