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)

CB 1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] has been the subject of continued interest for over 30 years. As an anti-cancer agent, it represents one of the very few examples of a compound that shows real anti-tumor selectivity. Unfortunately, for the treatment of human disease, this anti-tumor selectivity was seen only in certain rat tumors. The basis for the anti-tumor selectivity of CB 1954 is that it is a prodrug that is enzymatically activated to generate a difunctional agent, which can form DNA-DNA interstrand crosslinks. The bioactivation of CB 1954 in rat cells involves the aerobic reduction of its 4-nitro group to a 4-hydroxylamine by the enzyme NQO1 (DT-diaphorase). The human form of NQO1 metabolizes CB 1954 much less efficiently than rat NQO1. Thus human tumors are insensitive to CB 1954. In view of the proven success of CB 1954 in the rat system, it would be highly desirable to re-create its anti-tumor activity in man. This has led to the development of CB 1954 analogs and other prodrugs activated by nitroreduction such, as those based on a self-immolative activation mechanism. A gene therapy-based approach for targeting cancer cells and making them sensitive to CB 1954 and related compounds has been developed. VDEPT (gene-directed enzyme prodrug therapy) has been used to express an E. coli nitroreductase in tumor cells and human tumor cells transduced to express this enzyme are very sensitive to prodrugs activated by nitroreduction. CB 1954 is in clinical trial for this application. Recently it has been shown that a latent nitroreductase is present in some human tumors. This is NQO2--an enzyme that requires for activity, the non-biogenic compound dihydronicotinamide riboside (NRH) as a cosubstrate. When active, NQO2 is 3000 times more effective than human DT-diaphorase in the reduction of CB 1954. NRH and reduced pyridinium derivatives that, like NRH, act as co-substrates for NQO2, produce a dramatic increase in the cytotoxicity of CB 1954 against human cell lines in vitro and its anti-tumor activity against certain human xenografts in vivo. NQO2 activity is substantially raised in tumor samples from colorectal and hepatoma patients (up to 14-fold). A phase I clinical trial of an NQO2 co-substrate with CB 1954 is scheduled.
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PMID:CB 1954: from the Walker tumor to NQO2 and VDEPT. 1452 7

Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may contribute to Parkinson's disease (PD) pathogenesis. The quinone oxidoreductases, nicotinamide adenine dinucleotide (phosphate) (NAD[P]H): quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) detoxify quinones and quinonoid compounds. We investigated associations of genetic polymorphisms of NQO1 (C609T) and NQO2 (I/D, 29 base pairs) with PD in a population-based case-control study of 190 idiopathic PD cases and 305 unrelated controls matched on age and sex. No associations were detected for either gene variant or for any allele combinations.
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PMID:No associations between Parkinson's disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes. 1569 56

Quinone oxidoreductases (NQO1 and NQO2) are cytosolic proteins that catalyze metabolic reduction of quinones and its derivatives to protect cells against redox cycling and oxidative stress. In humans, a high percentage of individuals with myeloid and other types of leukemia are homo- and heterozygous for a null mutant allele of NQO1. The NQO2 locus is also highly polymorphic in humans. Recently, we generated NQO1-/- and NQO2-/- mice deficient in NQO1 and NQO2 protein and activity, respectively. These mice showed no detectable developmental abnormalities and were indistinguishable from wild type mice. Interestingly, all the mice lacking expression of NQO1 and NQO2 protein demonstrated myelogenous hyperplasia of the bone marrow and increased granulocytes in the peripheral blood. Decreased apoptosis contributed to myelogenous hyperplasia. The studies on short-term exposure of NQO1-/- mice to benzene demonstrated substantially greater benzene-induced toxicity, as compared to wild type mice.
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PMID:Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity. 3283 29

Resveratrol (trans-3,4',5-trihydroxystilbene) is a grape-derived polyphenol under intensive study for its potential in cancer prevention. In the case of cultured human melanoma cells, no one to our knowledge has investigated whether resveratrol exerts similar anti-proliferative activities in cells with different metastatic potential. Therefore, we examined the effects of this polyphenol on the growth of weakly metastatic Line IV clone 3 and on autologous, highly metastatic Line IV clone 1 cultured melanoma cells. Comparable inhibition of growth and colony formation resulted from treatment by resveratrol in both cell lines. Flow cytometric analysis revealed that resveratrol-treated clone 1 cells had a dose-dependent increase in S phase and a concomitant reduction in the G(1) phase. No detectable change in cell cycle phase distribution was found in similarly treated clone 3 cells. Western blots demonstrated a significant increase in the expression of the tumor suppressor gene p53, without a commensurate change in p21 and several other cell cycle regulatory proteins in both cell types. Chromatography of Line IV clone 3 and clone 1 cell extracts on resveratrol affinity columns revealed that the basal expression of dihydronicotinamide riboside quinone reductase 2 (NQO2) was higher in Line IV clone 1 than clone 3 cells. Levels of NQO2 but not its structural analog NQO1 were dose-dependently increased by resveratrol in both cell lines. We propose that induction of NQO2 may relate to the observed increased expression of p53 that, in turn, contributes to the observed suppression of cell growth in both melanoma cell lines.
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PMID:Inhibition of melanoma cell proliferation by resveratrol is correlated with upregulation of quinone reductase 2 and p53. 1599 43

Several lines of evidence suggest that genetic factors contribute to the vulnerability of drug abuse such as methamphetamine (MAP), and that dopamine-quinones produced by administration of MAP may be involved in the mechanism of MAP-related symptoms. The detoxification of quinones is catalyzed by a family of proteins designated as quinone oxidoreductases (NQOs). We analysed the polymorphisms of NQO1 and NQO2 genes to elucidate the association with genetic vulnerability to MAP abuse in Japan. The genotype and allele frequencies for the polymorphism (Pro187Ser) of the NQO1 gene did not differ between each subgroup of patients and controls. In contrast, the genotype frequency for the insertion/deletion (I/D) polymorphism in the promoter region of the NQO2 gene was a significant (p = 0.038) difference between patients with prolonged-type MAP psychosis and controls. This study suggests that the NQO2 gene polymorphism contributes to the aetiology of MAP-related psychosis in Japanese.
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PMID:Functional polymorphism of the NQO2 gene is associated with methamphetamine psychosis. 1619 66

The NAD(P)H:quinone acceptor oxidoreductase (NQO) gene family belongs to the flavoprotein clan and, in the human genome, consists of two genes (NQO1 and NQO2). These two genes encode cytosolic flavoenzymes that catalyse the beneficial two-electron reduction of quinones to hydroquinones. This reaction prevents the unwanted one-electron reduction of quinones by other quinone reductases; one-electron reduction results in the formation of reactive oxygen species, generated by redox cycling of semiquinones in the presence of molecular oxygen. Both the mammalian NQO1 and NQO2 genes are upregulated as a part of the oxidative stress response and are inexplicably overexpressed in particular types of tumours. A non-synonymous mutation in the NQO1 gene, leading to absence of enzyme activity, has been associated with an increased risk of myeloid leukaemia and other types of blood dyscrasia in workers exposed to benzene. NQO2 has a melatonin-binding site, which may explain the anti-oxidant role of melatonin. An ancient NQO3 subfamily exists in eubacteria and the authors suggest that there should be additional divisions of the NQO family to include the NQO4 subfamily in fungi and NQO5 subfamily in archaebacteria. Interestingly, no NQO genes could be identified in the worm, fly, sea squirt or plants; because these taxa carry quinone reductases capable of one- and two-electron reductions, there has been either convergent evolution or redundancy to account for the appearance of these enzyme functions whenever they have been needed during evolution.
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PMID:Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. 1659 77

NAD(P)H/NRH:quinone oxidoreductases (NQO1 and NQO2) protect against oxidative stress and neoplasia. Cross-breeding of NQO1-/- with NQO2-/- mice generated double-knockout (DKO) mice. DKO mice were born normal yet showed myelogenous hyperplasia as observed in single-knockout mice. DKO mice also showed bronchial-associated lymphoid tissue (BALT) that increased in number and size with age. BALT was absent in wild-type and single-knockout mice. Further analysis demonstrated infiltration of neutrophils and macrophages in BALT and significant increases in the serum cytokines TNFalpha, IL-6, and IL-1beta and increased expression of iNOS and higher nitric oxide in lung macrophages. The development of BALT in DKO mice presumably led to the release of cytokines and higher lung macrophage activation, because histologically spleen, thymus, and blood cultures and urine analysis showed absence of infection. Additionally, the DKO mice upon exposure to hyperoxia demonstrated severe intra-alveolar edema and perivascular inflammation and massive infiltration with neutrophils, compared with wild-type mice. These results suggest that NQO1 and NQO2 combined protect mice against lung inflammation, BALT, and hyperoxic lung injury.
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PMID:BALT development and augmentation of hyperoxic lung injury in mice deficient in NQO1 and NQO2. 1667 22

Melatonin has been shown to have oncostatic effects on malignant melanoma in vitro and in vivo. We studied the growth suppressive effects of melatonin over a wide range of concentrations in four melanoma cell lines (SBCE2, WM-98, WM-164 and SKMEL-188) representative for different growth stages and phenotype. Melanoma cells were incubated with melatonin 10(-12)-10(-3) M, and proliferation and clonogenicity was assessed at 12 h and 14 days, respectively. We also determined the expression of cytosolic quinone oxidoreductases NQO1, NQO2 (known as MT3 receptor) and nuclear receptor RORalpha by RT-PCR. Melatonin at pharmacological concentrations (10(-3)-10(-7) M) suppressed proliferation in all melanoma cell lines. In SKMEL-188 cells cultured in serum-free media, melatonin at low concentrations (10(-12)-10(-10) M) also slightly attenuated the proliferation. The effects of pharmacological doses of melatonin were confirmed in the clonogenic assay. Expression of NQO1 was detected in all cell lines, whereas NQO2 and nuclear receptor RORalpha including its isoform RORalpha4 were present only in SBCE2, WM-164 and WM-98. Thus, melatonin differentially suppressed proliferation in melanoma cell lines of different behaviour. The intensity of the oncostatic response to melatonin could be related to the cell-line specific pattern of melatonin cellular receptors and cytosolic binding protein expression.
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PMID:Oncostatic effects of the indole melatonin and expression of its cytosolic and nuclear receptors in cultured human melanoma cell lines. 1686 83

Benzo(a)pyrene (BaP) is a known human carcinogen and a suspected breast cancer complete carcinogen. BaP is metabolized by several metabolic pathways, some having bioactivation and others detoxification properties. BaP-quinones (BPQs) are formed via cytochrome P450 and peroxidase dependent pathways. Previous studies by our laboratory have shown that BPQs have significant growth promoting and anti-apoptotic activities in human MCF-10A mammary epithelial cells examined in vitro. Previous results suggest that BPQs act via redox-cycling and oxidative stress. However, because two specific BPQs (1,6-BPQ and 3,6-BPQ) differed in their ability to produce reactive oxygen species (ROS) and yet both had strong proliferative and EGF receptor activating activity, we utilized mRNA expression arrays and qRT-PCR to determine potential pathways and mechanisms of gene activation. The results of the present studies demonstrated that 1,6-BPQ and 3,6-BPQ activate dioxin response elements (DRE, also known as xenobiotic response elements, XRE) and anti-oxidant response elements (ARE, also known as electrophile response elements, EpRE). 3,6-BPQ had greater DRE activity than 1,6-BPQ, whereas the opposite was true for the activation of ARE. Both 3,6-BPQ and 1,6-BPQ induced oxidative stress-associated genes (HMOX1, GCLC, GCLM, and SLC7A11), phase 2 enzyme genes (NQO1, NQO2, ALDH3A1), PAH metabolizing genes (CYP1B1, EPHX1, AKR1C1), and certain EGF receptor-associated genes (EGFR, IER3, ING1, SQSTM1 and TRIM16). The results of these studies demonstrate that BPQs activate numerous pathways in human mammary epithelial cells associated with increased cell growth and survival that may play important roles in tumor promotion.
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PMID:Activation of dioxin response element (DRE)-associated genes by benzo(a)pyrene 3,6-quinone and benzo(a)pyrene 1,6-quinone in MCF-10A human mammary epithelial cells. 1746 51

Aging is often associated with decline of memory function. Aged animals, like humans, can naturally develop memory impairments and thus represent a useful model to investigate genes involved in long-term memory formation that are differentially expressed between aged memory-impaired (AI) and aged memory-unimpaired (AU) animals following stimulation in a spatial memory task. We found that alterations in hippocampal gene expression of transthyretin (TTR), calcineurin, and NAD(P)H dehydrogenase quinone 2 (NQO2) were associated with memory deficits in aged animals. Decreased TTR gene expression could be attributed at least partially to diminish activity of C/EBP immediate-early gene cascade initiated by CREB since protein levels of C/EBP, a transcription factor regulating both TTR and NQO2 expression, was decreased in AI animals. Memory deficits were also found during aging in mice lacking TTR, a retinol transporter known to prevent amyloid-beta aggregation and plaque formation as seen in Alzheimer's disease. Treatment with retinoic acid reversed cognitive deficits in these knock-out mice as well as in aged rats. Our study provides genetic, behavioural and molecular evidence that TTR is involved in the maintenance of normal cognitive processes during aging by acting on the retinoid signalling pathway.
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PMID:Transthyretin: a key gene involved in the maintenance of memory capacities during aging. 1751 93


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