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

Metabolic enzymes involved in benzene activation or detoxification, including NAD(P)H, quinone oxidoreductase 1 (NQO1), cytochrome P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase mu-1 (GSTM1), and glutathione-S-transferase theta-1 (GSTT1), were studied for their roles in human susceptibility to benzene poisoning. The potential interactions of these metabolic enzymes with lifestyle factors such as cigarette smoking and alcohol consumption were also explored. We studied 156 benzene-poisoning patients and 152 workers occupationally exposed to benzene in South China. Sequencing, denaturing HPLC, restriction fragment-length polymorphism, and polymerase chain reaction were used to detect polymorphisms on the promoters and complete coding regions of NQO1, CYP2E1, MPO, and the null genotypes of GSTM1 and GSTT1. Seventeen single nucleotide polymorphisms (SNPs) were identified in NQO1, CYP2E1, and MPO genes, including 6 novel SNPs in CYP2E1 and MPO. Of the subjects who smoked and drank alcohol, an 8.15-fold [95% confidence interval (CI), 1.43-46.50] and a 21.50-fold (95% CI, 2.79-165.79) increased risk of benzene poisoning, respectively, were observed among the subjects with two copies of NQO1 with a C-to-T substitution in cDNA at nucleotide 609 (c.609 C>T variation; i.e., NQO1 c.609 T/T) compared to those with the heterozygous or wild (NQO1 c.609 C/T and c.609 C/C) genotypes. Our data also indicated that individuals with CYP2E1 c.-1293 C/C and c.-1293 G/C, and NQO1 c.609 T/T, and GSTT1 null genotypes tended to be more susceptible to benzene toxicity. Our results suggest that the combined effect of polymorphisms in NQO1, CYP2E1, and GSTT1 genes and lifestyle factors might contribute to benzene poisoning.
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PMID:Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning. 1246 Aug

The etiology of acute myeloid leukemia (AML) is largely unknown. Biologic and epidemiologic data implicate exogenous toxicants, including cytotoxic drugs, benzene, radiation, and cigarette smoking. Allelic variation in genes encoding enzymes such as NADP(H) quinone oxidoreductase (NQO1) and glutathione S-transferase T1 (GSTT1) that metabolize environmental toxicants predispose to subtypes of AML, including therapy-related AML. We assayed NRAS oncogene mutation and FLT3 internal tandem duplication in 447 AML patients with an abnormal karyotype treated in Medical Research Council (MRC) AML clinical trials. Functional allelic variant frequencies in genes encoding carcinogen-metabolizing enzymes GSTT1, GSTM1, CYP1A1, CYP2D6, CYP2C19, SULT1A1, and NQO1 were previously determined for this cohort. FLT3 internal tandem duplication (ITD) frequency was 17%, and NRAS mutation 12% for the entire cohort. The 2 mutations were found together in only 4 patients. No association was found between enzyme allelic variant frequencies and the presence of FLT3 ITD for the entire cohort or within cytogenetic subgroups. CYP1A1*2B (Val) high-inducibility variant allele was overrepresented in patients with NRAS mutation compared with no mutation, for (1) the entire AML cohort (n = 8/53 vs 26/371; odds ratio [OR] = 2.36; 95% confidence interval [CI] 1.01-5.53) and (2) the poor-risk karyotype group (n = 6/14 vs 4/89; OR = 15.94; 95% CI 3.71-68.52) comprising patients with partial/complete deletion of chromosome 5 or 7, or abnormalities of chromosome 3. The CYP1A1*2B allele may predispose to the development of these subgroups of AML by augmented phase 1 metabolism to highly reactive intermediates of CYP1A1 substrates, including polycyclic aromatic hydrocarbons, or by generation of oxidative stress as a metabolic by-product.
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PMID:CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated with FLT3 internal tandem duplication. 1246 38

Benzene is one of wildly used chemicals. Long-term exposure to benzene causes hematotoxicities and further, the development of including anemia, myelodysplastic syndrome (MDS), aplastic anemia, etc., with the leukemia as the worst. People vary greatly in their susceptibility to adverse health outcomes from benzene exposure. The author reviewed the relationship between genetic polymorphism of I metabolic enzymes(CYP2E1, NQO1, MPO) and II metabolic enzymes(GST, PST) involving benzene metabolite and interindividual variation in their genetic susceptibility to hematotoxicity from benzene exposure in this paper.
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PMID:[Individual susceptibility to hematotoxicity from benzene exposure and the genetic polymorphism of metabolic enzymes]. 1256 53

The cytokinesis-block micronucleus (MN) assay in peripheral lymphocytes was used to assess the genetic effects of the occupational exposure to traffic fumes in policemen from the Municipality of Rome. The study population consisted of 192 subjects engaged in traffic control (exposed, 134 subjects), or in office work (controls, 58 subjects). Groups were balanced for age, gender, and smoking habits. The average benzene exposure during the workshift was 9.5 and 3.8 microg/m(3) in exposed individuals and controls, respectively. All subjects were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, and DT-diaphorase polymorphisms. The incidence of micronuclei and micronucleated cells was recorded in 1,000 binucleated cells harvested 66 hr after mitogen stimulation. Regression analysis of data showed that MN frequency was mainly modulated by the age (P = 0.001) and gender (P = 0.001) of the study subjects (relatively higher in the elderly and females), whereas it was unaffected by the occupational exposure to traffic fumes and smoking habits. A weak (P = 0.02) association between lower MN frequency and the GSTM1 null genotype was also observed. In order to improve the sensitivity of the method to excision-repairable lesions, a modified protocol, with exposure of cells to the repair inhibitor cytosine arabinoside (Ara-C) during the first 16 hr of growth, was applied to 78 subjects (46 exposed and 32 controls). The results confirmed the higher MN frequency in females (P < 0.05), but failed to demonstrate any significant effect of chemical exposure (occupational or related to smoking habits). When the frequency of MN induced by Ara-C (i.e., spontaneous values subtracted) was considered, a significant inverse correlation with age was observed (P = 0.005), possibly related to the age-dependent decrease in repair proficiency.
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PMID:Analysis of micronuclei in peripheral blood lymphocytes of traffic wardens: effects of exposure, metabolic genotypes, and inhibition of excision repair in vitro by ARA-C. 1260 82

Enzymes that activate and detoxify benzene are likely genetic determinants of benzene-induced toxicity.NAD(P)H: quinone oxidoreductase-1 (NQO1) detoxifies benzoquinones, proposed toxic metabolites of benzene. NQO1 deficiency in humans is associated with an increased risk of leukemia, specifically acute myelogenous leukemia, and benzene poisoning. We examined the importance of NQO1 in benzene-induced toxicity by hypothesizing that NQO1-deficient (NQO1-/-) mice are more sensitive to benzene than mice with wild-type NQO1 (NQO1+/+; 129/Sv background strain). Male and female NQO1-/- and NQO1+/+ mice were exposed to inhaled benzene (0, 10, 50, or 100 ppm) for 2 weeks, 6 h/day, 5 days/week. Micronucleated peripheral blood cells were counted to assess genotoxicity. Peripheral blood counts and bone marrow histology were used to assess hematotoxicity and myelotoxicity. p21 mRNA levels in bone marrow cells were used as determinants of DNA damage response. Female NQO1-/- mice were more sensitive (6-fold) to benzene-induced genotoxicity than the female NQO1+/+ mice. Female NQO1-/- mice had a 9-fold increase (100 versus 0 ppm) in micronucleated reticulocytes compared with a 3-fold increase in the female NQO1+/+ mice. However, the induced genotoxic response in male mice was similar between the two genotypes (> or = 10-fold increase at 100 ppm versus 0 ppm). Male and female NQO1-/- mice exhibited greater hematotoxicity than NQO1+/+ mice. p21 mRNA levels were induced significantly in male mice (>10-fold) from both strains and female NQO1-/- mice (> 8-fold), which indicates an activated DNA damage response. These results indicate that NQO1 deficiency results in substantially greater benzene-induced toxicity. However, the specific patterns of toxicity differed between the male and female mice.
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PMID:Genetic susceptibility to benzene-induced toxicity: role of NADPH: quinone oxidoreductase-1. 1261 5

The evolution of higher organisms from anaerobic to aerobic living has promoted an elaborate mechanism of defense against potentially toxic oxidants. Many environmental toxicants implicated in the pathogenesis of myelodysplastic syndromes (MDS), including benzene and ionizing radiation, exert toxicity via pro-oxidant mechanisms. The emerging data suggest a probable genetic susceptibility to environmental carcinogenesis through functional polymorphic variants in enzymes that metabolize toxicants and/or protect against oxidative stress. The most studied enzyme is NAD(P)H:quinone oxidoreductase (NQO1). CD34+ cells from individuals homozygous for the NQO1 C609T nonfunctional allelic variant are incapable of enzyme induction following exposure to benzene, thus potentially increasing the hematotoxicity of benzene metabolites. Serologic and molecular markers of oxidative stress are present in many patients with MDS and include an increased concentration of the lipid peroxidation product malondialdehyde and the presence of oxidized bases in CD34+ cells. Potential mechanisms of oxidative stress include mitochondrial dysfunction via iron overload and mitochondrial DNA mutation, systemic inflammation, and bone marrow stromal defects. The biological activity of the antioxidant aminothiol amifostine in vivo suggests that these pathways may be meaningful targets for future therapy in MDS patients.
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PMID:Oxidative stress and the myelodysplastic syndromes. 1277 21

Benzene has been implicated as an environmental risk factor in leukaemia and other haematological diseases. Relationships between urban benzene exposure, oxidative DNA damage and polymorphisms in metabolism enzymes were examined in 40 volunteers living and working in Copenhagen. Personal exposures to benzene, toluene and methyl tert-butyl ether (MTBE) were monitored during a 5-day period. DNA damage was measured by 7-hydro-8-oxo-2'-deoxyguanosine (8-oxodG) in lymphocyte DNA and urine and by comet assay with use of fapyguanine glycosylase (FPG) and endonuclease III (ENDO). Excretion of the benzene metabolites trans,trans-muconic acid (ttMA) and S-phenylmercapturic acid (S-PMA) were measured in urine. Polymorphisms in glutathione-S-transferases T1 (GSTT1), M1 (GSTM1) and P1 (GSTP1) and NAD(P)H:quinone oxidoreductase (NQO) were determined. Median exposures to benzene, toluene and MTBE were 2.5, 18.7 and 0.86 microg/m(3). No significant correlations between external benzene exposure and any of the biomarkers were found. However, a significant correlation between S-PMA excretion and 8-oxodG in lymphocytes was found (R(s)=0.39). Men were found to excrete significantly more ttMA than the women did and ttMA excretion in men was found to be significantly associated with external benzene exposure (R=0.53, P=0.025). In addition, ttMA and S-PMA excretion was significantly higher in subjects with the NQO+/-genotype compared with subjects with the wild type (P=0.004 and P=0.011, respectively). Even though there are some limitations in this study due to the low range of benzene exposure and biomarker concentrations as well as a small number of subjects, these results could suggest that even at ambient concentrations exposure to benzene could have genotoxic effects in susceptible individuals.
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PMID:Urban benzene exposure and oxidative DNA damage: influence of genetic polymorphisms in metabolism genes. 1279 93

Exposure to ambient air pollution has been associated with cancer. Ambient air contains a complex mixture of toxics, including particulate matter (PM) and benzene. Carcinogenic effects of PM may relate both to the content of PAH and to oxidative DNA damage generated by transition metals, benzene, metabolism and inflammation. By means of personal monitoring and biomarkers of internal dose, biologically effective dose and susceptibility, it should be possible to characterize individual exposure and identify air pollution sources with relevant biological effects. In a series of studies, individual exposure to PM(2.5), nitrogen dioxide (NO(2)) and benzene has been measured in groups of 40-50 subjects. Measured biomarkers included 1-hydroxypyrene, benzene metabolites (phenylmercapturic acid (PMA) and trans-trans-muconic acid (ttMA)), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine, DNA strand breaks, base oxidation, 8-oxodG and PAH bulky adducts in lymphocytes, markers of oxidative stress in plasma and genotypes of glutathione transferases (GSTs) and NADPH:quinone reductase (NQO1). With respect to benzene, the main result indicates that DNA base oxidation is correlated with PMA excretion. With respect to exposure to PM, biomarkers of oxidative damage showed significant positive association with the individual exposure. Thus, 8-oxodG in lymphocyte DNA and markers of oxidative damage to lipids and protein in plasma associated with PM(2.5) exposure. Several types of DNA damage showed seasonal variation. PAH adduct levels, DNA strand breaks and 8-oxodG in lymphocytes increased significantly in the summer period, requiring control of confounders. Similar seasonal effects on strand breaks and expression of the relevant DNA repair genes ERCC1 and OGG1 have been reported. In the present setting, biological effects of air pollutants appear mainly related to oxidative stress via personal exposure and not to urban background levels. Future developments include personal time-resolved monitors for exposure to ultrafine PM and PM(2.5,) use of GPS, as well as genomics and proteomics based biomarkers.
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PMID:Linking exposure to environmental pollutants with biological effects. 1464 27

In this chapter, we apply the molecular epidemiological paradigm of biomarkers of exposure, early effect and susceptibility to causal models of leukaemia and lymphoma. The aim is to enhance the development of biomarkers for use in studying the causes of these haematopoeitic cancers in the general population. Two causal models of acute myeloid leukaemia are discussed in detail: chemotherapy-induced and benzene-induced acute myeloid leukaemia. Specific chromosomal changes found in acute myeloid leukaemia may serve as useful biomarkers of early effect in these models, and genetic variants in glutathione S-transferases, NQO1 and DNA-repair enzymes may serve as useful biomarkers of susceptibility. Several causal models of lymphoma exist in which biomarkers could be developed and validated. These include human immunodeficiency virus (HIV) immunosuppression, families with inherited disorders and workers exposed to petroleum products, pesticides or organochlorines. Biomarkers of early effect could include markers of DNA double-strand breaks and aberrant V(D)J recombination, and susceptibility may be related to polymorphisms in genes controlling DNA repair and immunological status. We predict that biomarkers of susceptibility will continue to be studied in the case-control format, perhaps in large pooled studies, but that for biomarkers of early effect, there will be a move away from the study of diseased populations to the study of individuals 'at risk' in the causal models described above.
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PMID:Causal models of leukaemia and lymphoma. 1505 7

Benzene and its metabolites damage human lymphocytes, resulting in chromosomal aberrations and aneuploidy. Polymorphisms in the genes for benzene-metabolizing enzymes have been implicated in benzene-associated haematotoxicity. In this study, we examined the specificity of benzene-induced aneuploidy and the influence of genetic polymorphisms (GSTM1, GSTT1, GSTP1, NAT2, NQO1 and CYP2E1) on chromosomal aberrations. In total, 82 benzene-exposed workers from a coke oven plant and 76 matched controls were examined. The benzene concentration in the work-place air ranged from 0.014-0.743 p.p.m. (geometric mean 0.557 p.p.m.). Benzene exposure was associated with significant increases in both monosomy and trisomy of chromosomes 8 and 21. Translocations between chromosomes 8 and 21 [t(8:21)] were eight-fold more frequent in the high-level exposure group compared to the control group. Multiple regression analysis indicated that the frequencies of chromosome aberrations were significantly associated with benzene exposure and polymorphisms in the metabolic enzyme genes. A particular subset of genotypes, which included the GSTM1-null and GSTT1-null genotypes, the slow acetylator type of NAT2, a variant of the NQO1 genotype and the CYP2E1 DraI and RsaI genotypes, were either separately, or in combination, associated with increased frequencies of aneuploidy among the benzene-exposed individuals after adjustments for age, alcohol consumption and smoking. These results suggest that polymorphisms in the genes for benzene-metabolizing enzymes influence the susceptibility of individuals to chromosomal aberrations in relation to benzene exposure.
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PMID:Chromosomal aberrations in workers exposed to low levels of benzene: association with genetic polymorphisms. 1522 77


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