Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genes involved in metabolism of environmental chemical exposures exhibit sequence variability that may mediate the risk of non-Hodgkin's lymphoma. We evaluated associations between non-Hodgkin's lymphoma and 15 variants in AHR, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2E1, GSTP1, GSTM3, EPHX1, NQO1, and PON1. Cases were identified from four Surveillance, Epidemiology, and End Results registries in the United States, and population-based controls were identified through random-digit dialing and Medicare eligibility files. Metabolic gene variants were characterized for the 1,172 (89% of total) cases and 982 (93%) controls who provided biological samples for genotyping. Subjects who were heterozygous or homozygous for the cytochrome P450 gene variant CYP1B1 V432L G allele were at slightly greater risk of non-Hodgkin's lymphoma [odds ratio (OR), 1.27; 95% confidence interval (95% CI), 0.97-1.65]; these results were consistent across B-cell lymphoma subtypes and among both non-Hispanic White and Black subjects, although not statistically significant. The CYP2E1 -1054T allele was associated with decreased risk of non-Hodgkin's lymphoma (CT and TT genotypes combined OR, 0.59; 95% CI, 0.37-0.93), and this pattern was observed among all histologic subtypes. The numbers of cases of particular subtypes were rather small for stable estimates, but we noted that the PON1 L55M AA allele, associated with slightly increased risk of non-Hodgkin's lymphoma (variant homozygotes OR, 1.36; 95% CI, 0.96-1.95), was most strongly associated with follicular non-Hodgkin's lymphoma and T-cell lymphoma, with ORs for variant homozygotes of 2.12 and 2.93, respectively. There was no overall association with non-Hodgkin's lymphoma for the other gene variants we examined. The modest effects we observed may reflect the context of exposures within the general population represented in our study.
...
PMID:Metabolic gene variants and risk of non-Hodgkin's lymphoma. 1698 26

Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1alpha (HNF1alpha) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1alpha germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1alpha-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1alpha-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1alpha-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1alpha mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line-inactivating mutations might increase the incidence of HCA in women with HNF1alpha mutations.
...
PMID:Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma. 1736 80

Previous studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation.
...
PMID:Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. 1750 24

Spanish black radish (Raphanus sativus L. var. niger) is a member of the Cruciferae family that also contains broccoli and Brussels sprouts, well-known to contain health-promoting constituents. Spanish black radishes (SBR) contain high concentrations of a glucosinolate unique to the radish family, glucoraphasatin, which represents >65% of the total glucosinolates present in SBR. The metabolites of glucosinolates, such as isothiocyanates, are implicated in health promotion, although it is unclear whether glucosinolates themselves elicit a similar response. The crude aqueous extract from 0.3 to 3 mg of dry SBR material increased the activity of the phase II detoxification enzyme quinone reductase in the human hepatoma HepG2 cell line with a maximal effect at a concentration of 1 mg/mL. Treatment of HepG2 cells with the crude aqueous extract of 1 mg of SBR per mL also significantly induced the expression of mRNA corresponding to the phase I detoxification enzymes: cytochrome P450 (CYP) 1A1, CYP1A2, and CYP1B1 as well as the phase II detoxification enzymes: quinone reductase, heme oxygenase 1, and thioredoxin reductase 1. Previous studies have shown that the myrosinase metabolites of different glucosinolates vary in their ability to induce detoxification enzymes. Here, we show that while glucoraphasatin addition was ineffective, the isothiocyanate metabolite of glucoraphasatin, 4-methylthio-3-butenyl isothiocyanate (MIBITC), significantly induced phase II detoxification enzymes at a concentration of 10 microM. These data demonstrate that the crude aqueous extract of SBR and the isothiocyanate metabolite of glucoraphasatin, MIBITC, are potent inducers of detoxification enzymes in the HepG2 cell line.
...
PMID:Aqueous extract from Spanish black radish (Raphanus sativus L. Var. niger) induces detoxification enzymes in the HepG2 human hepatoma cell line. 1761 35

Xanthohumol (XN), the principal prenylated flavonoid in the hop plant, Humulus lupulus L., is suggested to have cancer chemo-preventive activities. Its mechanisms of protection have been proposed to be inhibition of metabolic activation, induction of detoxifying enzymes and antioxidant activity. Our previous study showed that XN efficiently protected human hepatoma HepG2 cells against the genotoxic effects of two pro-carcinogens (2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and benzo(a)pyrene (BaP)) that are dependent on cytochrome P450 (CYP) mediated metabolic activation, and against genotoxic effects of the oxidative damage inducing tert-butyl hydroperoxide (tBOOH). In the present study, we investigated the antigenotoxic effects of XN in precision-cut rat liver slices. Using the comet assay, we detected that at non-cytotoxic concentrations (0.01-10 microM) XN completely prevented IQ and BaP-induced DNA damage. The protective effects of XN against tBOOH-induced DNA damage was less efficient; the maximal 50% reduction of DNA damage was observed at 0.1 microM XN. In rat microsomes, XN (0.001-10 microM) inhibited CYP1A activity (7-ethoxycoumarin (7EC) de-ethylation) in a concentration-dependent manner. Surprisingly, no inhibition of 7EC metabolism by XN was observed in rat liver slices. XN also did not have any influence on mRNA expression of the enzymes CYP1A2 and quinone reductase (QR). These results indicate that inhibition of metabolic activation of pro-carcinogens by CYP1A is not likely to be the mechanism of its antigenotoxic action. In conclusion, XN efficiently protects DNA against genotoxicity of IQ and BaP and against oxidative DNA damage. Although the mechanism of the protective effect of XN is unclear, our results indicate that XN exhibits antigenotoxic effects in fresh liver tissue and provide additional evidence for the cancer preventive potential of XN.
...
PMID:Antigenotoxic effect of Xanthohumol in rat liver slices. 1798 Oct 5

Sulindac is a nonsteroidal antiinflammatory drug that has been demonstrated to be a potent chemopreventive agent against colorectal cancer in both human and animal models. In vivo, sulindac may be reversibly reduced to the active antiinflammatory compound, sulindac sulfide, or irreversibly oxidized to sulindac sulfone. Sulindac has also been shown to inhibit polycyclic aromatic hydrocarbon (PAH)-induced cancer, but the molecular mechanisms of its antitumor effect remain unclear. In this study, we investigated the effects of sulindac and its metabolites on the expression of enzymes that metabolize and detoxify PAHs in 2 human colon cancer cell lines, LS180 and Caco-2. Sulindac and sulindac sulfide induced a sustained, concentration-dependent increase in CYP enzyme activity as well as an increase in the mRNA levels of CYP1A1, CYP1A2 and CYP1B1. Sulindac and sulindac sulfide induced the transcription of the CYP1A1 gene, as measured by the level of heterogeneous nuclear CYP1A1 RNA and verified by the use of actinomycin D as a transcription inhibitor. Chromatin immunoprecipitation assays demonstrated that sulindac and sulindac sulfide also increased the nuclear level of activated aryl hydrocarbon receptor, the transcription factor which mediates CYP expression. Additionally, sulindac and both metabolites increased the activity and mRNA expression of the carcinogen detoxification enzyme NAD(P)H:quinone oxidoreductase, as well as the expression of UDP-glucuronosyltransferase mRNA. These results show an overall upregulation of carcinogen metabolizing enzymes in colon cancer cells treated with sulindac, sulindac sulfide and sulindac sulfone that may contribute to the established chemoprotective effects of these compounds.
...
PMID:Sulindac and its metabolites induce carcinogen metabolizing enzymes in human colon cancer cells. 1798 43

Metabolic activation of 17beta-estradiol (E2) to catechols and quinones together with lack of deactivation constitute risk factors in human breast carcinogenesis. E2-catchols are generated by cytochrome P450-dependent monooxygenases (CYPs). Deactivation of E2, E2-catechols, and E2-quinones is mediated by UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), catechol-O-methyltransferase (COMT), glutathione-S-transferase (GST), and NADPH-quinone-oxidoreductase (QR) isozymes, respectively. The aim of the present study was to quantify mRNA levels of E2-metabolizing isozymes expressed in MCF-7 cells cultured in the presence/absence of steroids by reverse transcription/competitive PCR in relation to the housekeeping gene hypoxanthine-guanine phosphoribosyltransferase and compare them with expression levels in normal human mammary gland (MG) and liver tissue. CYP1A1, 1B1, SULT1A1, 1A2, membrane-bound and soluble COMT, GSTT1, QR1, and UGT2B7 were detected in both tissues and MCF-7 cells; however, most enzymes were expressed at least tenfold higher in liver. Yet, CYP1B1 was expressed as high in breast as in liver and UGTs were not detected in MCF-7 cells cultured with steroids. MCF-7 cells cultured steroid-free additionally expressed CYP1A2 as well as UGT1A4, 1A8, and 1A9. Normal human liver but not MG expressed CYP1A2, 3A4, UGT1A1, 1A3, 1A4, 1A9, and SULT2A1. UGT1A8 was only detected in MCF7 cells but was not found in human liver. Thus, our study provides a comprehensive overview of expression levels of E2-metabolizing enzymes in a popular in vitro model and in human tissues, which will contribute to the interpretation of in vitro studies concerning the activation/deactivation of E2.
...
PMID:Gene expression of 17beta-estradiol-metabolizing isozymes: comparison of normal human mammary gland to normal human liver and to cultured human breast adenocarcinoma cells. 1849 89

Aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) are carcinogens present in tobacco smoke and functional polymorphisms in NAT2 and GSTM1 metabolizing genes are associated with increased bladder cancer risk. We evaluated whether genetic variation in other candidate metabolizing genes are also associated with risk. Candidates included genes that control the transcription of metabolizing genes [aryl hydrocarbon receptor (AHR), AHRR and aryl hydrocarbon nuclear translocator (ARNT)] and genes that activate/detoxify AA or PAH (AKR1C3, CYP1A1, CYP1A2, CYP1B1, CYP3A4, EPHX1, EPHX2, NQO1, MPO, UGT1A4, SULT1A1 and SULT1A2). Using genotype data from 1150 cases of urothelial carcinomas and 1149 controls from the Spanish Bladder Cancer Study, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, region and smoking status. Based on a test for trend, we observed 10 non-redundant single-nucleotide polymorphisms (SNPs) in five genes (AKR1C3, ARNT, CYP1A1, CYP1B1 and SULT1A2) significantly associated with bladder cancer risk. We observed an inverse association with risk for the AKR1C3 promoter SNP rs1937845 [OR (95% CI) for heterozygote and homozygote variant compared with common homozygote genotype were 0.86 (0.70-1.06) and 0.74 (0.57-0.96), respectively; P for trend = 0.02]. Interestingly, genetic variation in this region has been associated with lung, non-Hodgkin lymphoma and prostate cancer risk. Analysis of additional SNPs to capture most (approximately 90%) of common genetic variation in AKR1C3 and haplotype walking analyses based on all AKR1C3 SNPs (n = 25) suggest two separate regions associated with bladder cancer risk. These results indicate that genetic variation in carcinogen-metabolizing genes, particularly AKR1C3, could be associated with bladder cancer risk.
...
PMID:Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. 1863 53

Binding and activation of the aryl hydrocarbon receptor (AhR) is thought to be an essential step in the toxicity of the environmental pollutants dioxins and dioxin-like PCBs. However, also a number of natural compounds, referred to as NAhRAs (natural Ah-receptor agonists), which are present in, for example, fruits and vegetables, can bind and activate this receptor. To study their potential effects in humans, we first investigated the effect of the prototypical AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gene expression in ex vivo exposed freshly isolated human lymphocytes, and compared the resulting gene expression profile with those caused by the well-known NAhRA indolo[3,2-b]carbazole (ICZ), originating from cruciferous vegetables, and by a hexane extract of NAhRA-containing grapefruit juice (GJE). Only ICZ induced a gene expression profile similar to TCDD in the lymphocytes, and both significantly up-regulated CYP1B1 and TIPARP (TCDD-inducible poly (ADP-ribose) polymerase) mRNA. Next, we performed a human intervention study with NAhRA-containing cruciferous vegetables and grapefruit juice. The expression of the prototypical AhR-responsive genes CYP1A1, CYP1B1 and NQO1 in whole blood cells and in freshly isolated lymphocytes was not significantly affected. Also enzyme activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO), as judged by caffeine metabolites in urine, were unaffected, except for a small down-regulation of NAT2 activity by grapefruit juice. Examination of blood plasma with DR CALUX showed a 12% increased AhR agonist activity 3 and 24 h after consumption of cruciferous vegetables, but did not show a significant effect of grapefruit juice consumption. We conclude that intake of NAhRAs from food may result in minor AhR-related effects measurable in human blood and urine.
...
PMID:A human intervention study with foods containing natural Ah-receptor agonists does not significantly show AhR-mediated effects as measured in blood cells and urine. 1876 78

It is widely accepted that the cytotoxicity and genotoxicity of benzene results from the action of reactive metabolites. Therefore, genetic variation in metabolic enzyme genes may contribute to susceptibility to chronic benzene poisoning (CBP) in the exposed population. Using a case-control study that included 268 benzene-poisoned patients and 268 workers occupationally exposed to benzene in South China, we aimed to investigate the association between single-nucleotide polymorphisms in genes with phase I and II of metabolism and risk of CBP. The TaqMan technique was used to detect polymorphisms of CYP1A1, CYP1A2, CYP1B1, ADH1B, EPHX1, EPHX2, NQO1, MPO, GSTP1 and UGT1A6 genes. We also explored potential interactions of these polymorphisms with lifestyle factors such as cigarette smoking and alcohol consumption. A weak positive association was found between glutathione S-transferase pi-1 (GSTP1) rs1695 polymorphism and the risk of CBP (P = 0.046), but this association was not statistically significant (P = 0.117) after adjustment for potential confounders. Further analysis showed that the risk of CBP increased in the subjects with EPHX1 GGAC/GAGT diplotype (P = 0.00057) or AGAC/GAGT diplotype (P = 0.00086). In addition, we found that alcohol drinkers with the EPHX1 rs3738047 GA + AA genotypes and non-alcohol drinkers with the GSTP1 rs1695 AA genotype tended to be more susceptible to benzene toxicity. Our results suggest that genetic polymorphisms in EPHX1 may contribute to risk of CBP in a Chinese occupational population.
...
PMID:Polymorphisms in phase I and phase II metabolism genes and risk of chronic benzene poisoning in a Chinese occupational population. 1878 59


<< Previous 1 2 3 4 5 6 7 Next >>

---