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

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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)

Benzene is a ubiquitous occupational hematotoxin and leukemogen, but people vary in their response to this toxic agent. To evaluate the impact of interindividual variation in enzymes that activate (i.e., CYP2E1) and detoxify (i.e., NQO1) benzene and its metabolites, we carried out a case-control study in Shanghai, China, of occupational benzene poisoning (BP; i.e., hematotoxicity), which we show is itself strongly associated with subsequent development of acute nonlymphocytic leukemia and the related myelodysplastic syndromes (relative risk, 70.6; 95% confidence interval, 11.4-439.3). CYP2E1 and NQO1 genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fractional excretion of chlorzoxazone (fe(6-OH)) for 50 cases of BP and 50 controls. Subjects with both a rapid fe(6-OH). and two copies of the NQO1 609C-->T mutation had a 7.6-fold (95% confidence interval, 1.8-31.2) increased risk of BP compared to subjects with a slow fe(6-OH) who carried one or two wild-type NQO1 alleles. In contrast, the CYP2E1 PstI/RsaI polymorphism did not influence BP risk. This is the first report that provides evidence of human susceptibility to benzene-related disease. Further evaluation of susceptibility for hematotoxicity and hematological malignancy among workers with a history of occupational exposure to benzene is warranted.
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PMID:Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone. 923 Jan 85

NAD(P)H:quinone oxidoreductase (NQO1) converts benzene-derived quinones to less toxic hydroquinones and has been implicated in benzene-associated hematotoxicity. A point mutation in codon 187 (Pro to Ser) results in complete loss of enzyme activity in homozygous subjects, whereas those with 2 wild-type alleles have normal activity. The frequency of homozygosity for the mutant allele among Caucasians and African Americans is 4% to 5% but is higher in Hispanics and Asians. Using an unambiguous polymerase chain reaction (PCR) method, we assayed nonmalignant lymphoblastoid cell lines derived from 104 patients with myeloid leukemias; 56 had therapy-related acute myeloid leukemia (t-AML), 30 had a primary myelodysplastic syndrome (MDS), 9 had AML de novo, and 9 had chronic myelogenous leukemia (CML). All patients had their leukemia cells karyotyped. Eleven percent of the t-AML patients were homozygous and 41% were heterozygous for the NQO1 polymorphism; these proportions were significantly higher than those expected in a population of the same ethnic mix (P =.036). Of the 45 leukemia patients who had clonal abnormalities of chromosomes 5 and/or 7, 7 (16%) were homozygous for the inactivating polymorphism, 17 (38%) were heterozygous, and 21 (47%) had 2 wild-type alleles for NQO1. Thus, NQO1 mutations were significantly increased compared with the expected proportions: 5%, 34%, and 61%, respectively (P =.002). An abnormal chromosome no. 5 or 7 was observed in 7 of 8 (88%) homozygotes, 17 of 45 (38%) heterozygotes, and 21 of 51 (41%) patients with 2 wild-type alleles. Among 33 patients with balanced translocations [14 involving bands 11q23 or 21q22, 10 with inv(16) or t(15;17), and 9 with t(9;22)], there were no homozygotes, 15 (45%) heterozygotes, and 18 (55%) with 2 wild-type alleles. Whereas fewer than 3 homozygotes were expected among the 56 t-AML patients, 6 were observed; 19 heterozygotes were expected, but 23 were observed. The gene frequency for the inactivating polymorphism (0. 31) was increased approximately 1.4-fold among the 56 t-AML patients. This increase was observed within each of the following overlapping cohorts of t-AML patients: the 43 who had received an alkylating agent, the 27 who had received a topoisomerase II inhibitor, and the 37 who had received any radiotherapy. Thus, the frequency of an inactivating polymorphism in NQO1 appears to be increased in this cohort of myeloid leukemias, especially among those with t-AML or an abnormality of chromosomes 5 and/or 7. Homozygotes and heterozygotes (who are at risk for treatment-induced mutation or loss of the remaining wild-type allele in their hematopoietic stem cells) may be particularly vulnerable to leukemogenic changes induced by carcinogens.
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PMID:Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia. 1039 48

Several genetic polymorphisms in metabolic activation or detoxification enzymes have been associated with susceptibility to therapy-related leukemia and myelodysplastic leukemia (TRLIMDS). We analyzed gene polymorphisms of NAD(P)H:quinone oxidoreductase (NQOl), glutathione S-tranferase (GST)-MI and -TI, and CYP3A4, the enzymes of which are capable of metabolizing anticancer drugs, in 58 patients with TRL/MDS and in 411 patients with de novo acute myeloid leukemia (AML). Homozygous Ser/Ser genotype of NQOl at codon 187, causing loss of function, was more frequent in the patients with TRLIMDS (14 of 58, 24.1%; OR = 2.62) than in those with de novo AML (64 of 411, 15.6%), and control (16 of 150, 10.6%; P = 0.002). Allelic frequencies of NQOJ were different between TRL/ MDS and de novo AML (P = 0.01). In GST-MJ and -Ti, the incidence of homologous deletion was similar among the three groups. The polymorphism of the 5' promoter region of CYP3A4 was not found in persons of Japanese ethnicity. These results suggest that the NQOJ polymorphism is significantly associated with the genetic risk of TRLIMDS.
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PMID:Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/ myelodysplastic syndrome and de novo acute myeloid leukemia. 1105 Dec 61

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 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

The molecular pathogenesis of therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/MDS) remains uncertain. However, clonal haemopoiesis may develop following stem cell transplantation and precede the development of t-AML/MDS. Moreover, accelerated telomere shortening may be induced by replicative stress or oxidative damage, leading to genomic instability, and inactivating polymorphisms of the gene encoding NADPH-quinone oxidoreductase (NQO1) are more frequently observed in patients with t-AML. We studied clonal haemopoiesis, telomere length and NQO1 status in 146 patients receiving conventional chemotherapy for non-myeloid malignancies. Clonal haemopoiesis was demonstrated in eight of 98 (8%) patients. Telomere length was reduced in patients following chemotherapy (n = 52) compared with controls (n = 42) (P < 0.001), particularly in those with clonal haemopoiesis (P < 0.002). Whilst there was a trend towards telomere shortening in control subjects polymorphic for NQO1-187Ser (n = 12), chemotherapy-exposed patients polymorphic for the NQO1-187Ser allele (n = 29) had significantly shorter telomeres (P < 0.001). Furthermore, chemotherapy-treated patients with the NQO1-187Ser, polymorphism were more likely to develop clonal haemopoiesis than patients with wild type NQO1 (odds ratio = 7; 1.16-42.6). We conclude that a switch to clonal haemopoiesis may occur after conventional chemotherapy and lead to accelerated telomere shortening. Patients with the NQO1-187Ser polymorphism have an increased risk of developing both clonal haemopoiesis and telomere shortening, which may partly explain the predisposition to t-AML in NQO1-187Ser null individuals.
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PMID:Clonal haemopoiesis may occur after conventional chemotherapy and is associated with accelerated telomere shortening and defects in the NQO1 pathway; possible mechanisms leading to an increased risk of t-AML/MDS. 1519 33

Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) is a malignancy occurring after exposure to chemotherapy and/or radiotherapy. Polymorphisms involved in chemotherapy/radiotherapy response genes could be related to an increased risk of developing this neoplasia. We have studied 11 polymorphisms in genes of drug detoxification pathways (NQO1, glutathione S-transferase pi) and DNA repair xeroderma pigmentosum, complementation group (3) (XPC(3), X-ray repair cross complementing protein (1)), Nijmegen breakage syndrome (1), excision repair cross-complementing rodent repair deficiency, complementation group (5) and X-ray repair cross complementing protein (3) and in the methylene tetrahydrofolate reductase gene (MTHFR(2), 677C>T, 1298A>C), involved in DNA synthesis. The analyzed groups were a t-MDS/AML patients group (n=81) and a matched control group (n=64) treated similarly, and they did not develop t-MDS/AML. We found no significant differences when the groups were compared globally. However, when analysis was carried out according to the primary neoplasia involved, a significant association was observed between the MTHFR haplotype (single nucleotide polymorphisms 677 and 1298) and the risk of developing t-MDS/AML in the breast cancer patients group (P=0.016) and cyclophosphamide-treated hematological disease group (P=0.005). Risk haplotype was different for each case, corresponding to the 677T1298A haplotype after breast cancer treatment and the 677C1298C haplotype after hematological malignancy treatment. We postulate that such differences are related to variations in chemotherapy schemes between hematological and breast cancers and their differential interaction with the MTHFR route.
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PMID:Role of MTHFR (677, 1298) haplotype in the risk of developing secondary leukemia after treatment of breast cancer and hematological malignancies. 1747 81

The genetic background may modify the individual's risk of developing cancer. We performed a case-control study to test the impact of genomic polymorphisms of 9 genes involved in xenobiotics detoxification and DNA repair in myelodysplastic syndromes (MDS). Frequencies of polymorphic variants of RAD51, XRCC3, NQO1, GSTA1, GSTM1, GSTT1, CYP3A4 and XPD enzymes were similar in patients and controls. On the other hand, the GSTP1-105Val allele was associated to an increased risk of MDS (O.R. 1.66; p=0.04) and to higher probability of overall survival in the low/intermediate-1 IPSS risk group (p=0.008). The GSTP1-Ile105Val polymorphism is likely to influence MDS risk and prognosis.
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PMID:Polymorphisms of detoxification and DNA repair enzymes in myelodyplastic syndromes. 1902 52

Therapy-related myeloid neoplasms (t-MN) include acute myeloid leukemias and myelodysplastic syndromes arising in patients who have been treated with chemotherapy, radiation therapy, immunosuppressive agents or after documented exposure to environmental carcinogen. t-MN are defined according to the primary treatment and the corresponding genetic and molecular lesions. Chromosome(s) 7 and/or 5 monosomies or deletions are typical of alkylating agent-induced AML, while balanced translocations involving chromosome bands 11q23 and 21q22 are associated to preceeding therapy with DNA-topoisomerase II inhibitors. Antimetabolites, and in particular the immunosuppressive agents azathioprine and fludarabine, have also been recently associated to t-MN. Leukemias developing after benzene exposure are similar to t-MN and are characterized by chromosomal aberrations, which have been also observed among otherwise healthy benzene-exposed workers. Individual predisposing factors, including polymorphisms of detoxification and DNA-repair enzymes have been identified. Two genetic variants in key metabolizing enzymes, myeloperoxidase and NAD(P)H:quinone oxidoreductase, have been shown to influence susceptibility to benzene hematotoxicity. Combination of polymorphisms impairing detoxification and DNA repair may significantly increase therapy-related myeloid neoplasm risk. Among hematological malignancies, long-term survivors of Hodgkin's lymphoma are exposed to an increased t-MN risk, particularly when receiving MOPP-based and escalated-BEACOPP regimens, and when alkylators are combined to radiotherapy. Patients with lymphoma are at highest risk if total body irradiation followed by autologous stem cell transplantation is used as rescue or consolidation. The addition of granulocyte-colony stimulating factor (G-CSF) and radiotherapy plays a significant role in t-MN following treatment of childhood acute lymphoblastic leukemia. In solid tumors, treatment for breast cancer and germ-cell tumors has been associated with a 1-5% lifetime risk of t-MN.
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PMID:Incidence and susceptibility to therapy-related myeloid neoplasms. 2002 17

Molecular epidemiological studies have found new insights into the etiology of myelodysplastic syndromes (MDS). We analyzed the polymorphisms of 5 genes in 275 patients with primary MDS and 354 healthy controls in an attempt to identify candidate genetic risk factors for primary MDS in Chinese Han population. There was no difference in polymorphic variants of GSTM1, NQO1-C609T and XRCC3-C241T between the patients and controls. The homozygous variant C/C of RAD51-G135C was found to increase the susceptibility to MDS (OR, 4.13; p=0.001) and the risk of MDS association with structural abnormal karyotype (OR, 7.67; p=0.001). In addition, the null genotype of GSTT1 was correlated MDS patients with complex aberrant karyotype (OR, 3.25; p=0.012). These potential genetic predisposition suggested their possible involvement in the multistep pathogenesis of MDS.
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PMID:Detoxification and DNA repair genes polymorphisms and susceptibility of primary myelodysplastic syndromes in Chinese population. 2117 50


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