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)

Generation of radicals in vivo depends on metabolic activities. The reactions are usually influenced by (i) the presence and concentration of oxygen; (ii) the availability of transition metals (effects of binding and compartimentalization); (iii) the level of reductants and antioxidants (e.g. nutritional effects). The effects of radicals are thought to be due to (i) membrane damage (affecting passive or active transport through altered fluidity/function interrelationships, intercellular messenging through modifications in the synthesis of prostaglandins and leukotrienes); (ii) protein damage (e.g. affecting membrane transporters, channel proteins, receptor or regulatory proteins, immunomodulators); (iii) damage to DNA. Defense mechanisms consist of (i) prevention of the 'spreading' of primary damage by low molecular weight antioxidants (e.g. vitamin E, GSH, vitamin C, beta-carotene, uric acid); (ii) prevention or limitation of 'secondary' damage by enzymes (e.g. GSH-peroxidase, catalase, superoxide dismutase, DT-diaphorase) and/or chelators; (iii) repair processes, e.g. lipid degradation/membrane repair enzymes (phospholipases, peroxidases, some transferases and reductases), protein disposal or repair enzymes (proteases, GSSG-reductase), DNA degradation repair enzymes (exonuclease III, endonucleases III and IV, glycosylases, polymerases). Recent hypotheses on a messenging function of the superoxide anion O2- are discussed and possible implications of cross-reactions between O2- and nitric oxide (endothelium-derived relaxing factor EDRF) are shortly mentioned.
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PMID:Radical reactions in vivo--an overview. 228 Nov 32

In recent years it has become clear that various free radicals and related oxidants can cause serious damage to intracellular enzymes and other proteins. Several investigators have shown that in extreme cases this can result in an accumulation of oxidatively damaged proteins as useless cellular debris. In other instances, proteins may undergo scission reactions with certain radicals/oxidants, resulting in the direct formation of potentially toxic peptide fragments. Data has also been gathered (recently) demonstrating that various intracellular proteolytic enzymes or systems can recognize, and preferentially degrade, oxidatively damaged proteins (to amino acids). In this hypothesis paper I present evidence to suggest that proteolytic systems (of proteinases, proteases, and peptidases) may function to prevent the formation or accumulation of oxidatively damaged protein aggregates. Proteolytic systems can also preferentially degrade peptide fragments and may thus prevent a wide variety of potentially toxic consequences. I propose that many proteolytic enzymes may be important components of overall antioxidant defenses because they can act to ameliorate the consequences of oxidative damage. A modified terminology is suggested in which the primary antioxidants are such agents as vitamin E, beta-carotene, and uric acid and such enzymes as superoxide dismutase, glutathione peroxidase, and DT-diaphorase. In this classification scheme, proteolytic systems, DNA repair systems, and certain lipolytic enzymes would be considered as secondary antioxidant defenses. As secondary antioxidant defenses, proteolytic systems may be particularly important in times of high oxidative stress, during periods of (primary) antioxidant insufficiency, or with advancing age.
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PMID:Intracellular proteolytic systems may function as secondary antioxidant defenses: an hypothesis. 355 99

In the present study, we examined whether active oxygen formed in the process of 4-nitroquinoline 1-oxide (4NQO) reduction by DT-diaphorase could induce oxidative stress on the pulmonary nuclei. The rapid production of OH- radical-like species after the start of the 4NQO reduction was observed, and subsequent induction of nuclear lipid peroxidation occurred. In conjugation with this event, DNA damage estimated as DNA single strand breaks (DNA-SSB) increased in a time-dependent manner. The induction of this DNA damage was partially inhibited by mannitol or vitamin E treatment. These findings suggest that the active oxygen generated in the process of the 4NQO reduction can induce oxidative damage on the pulmonary nuclei.
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PMID:Active oxygen generated in the process of carcinogen metabolism can induce oxidative damage in nuclei. 762 Aug 30

We have used a model of dietary deficiency that leads to a chronic oxidative stress to evaluate responses that are adaptations invoked to boost cellular defense systems. Long-Evans hooded rats were fed with a diet lacking vitamin E (E) and selenium (Se) for 7 wk from weaning leading to animals deficient in both nutrients (-E -Se). In the absence of an electron donor, liver plasma membranes from these rats were more sensitive to lipid peroxidation, although they contained 40% greater amounts of ubiquinone than the plasma membranes from rats consuming diets with sufficient vitamin E and Se (+E +Se). The incubation of plasma membranes with NAD(P)H resulted in protection against peroxidation, and this effect was more pronounced in -E -Se membranes. Deficiency was accompanied by a twofold increase in redox activities associated with trans plasma membrane electron transport such as ubiquinone reductase and ascorbate free radical reductase. Staining with a polyclonal antibody against pig liver cytochrome b5 reductase, which acts as one ubiquinone reductase in the plasma membrane, showed an increased expression of the enzyme in membranes from -E -Se rats. Little DT-diaphorase activity was measured in +E +Se plasma membranes, but this activity was dramatically increased in -E -Se plasma membranes. No such increase was found in liver cytosols, which contained elevated activity of calcium-independent phospholipase A2. Thus, ubiquinone-dependent antioxidant protection in +E +Se plasma membranes is based primarily on NADH-cytochrome b5 reductase, whereas additional protection needed in -E -Se plasma membranes is supported by the increase of ubiquinone levels, increased expression of the cytochrome b5 reductase, and translocation of soluble DT-diaphorase to the plasma membrane. Our results indicate that, in the absence of vitamin E and Se, enhancement of ubiquinone-dependent reductase systems can fulfill the membrane antioxidant protection.
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PMID:Vitamin E and selenium deficiency induces expression of the ubiquinone-dependent antioxidant system at the plasma membrane. 983 56

We have studied the effects of dietary depletion of vitamin E and selenium on endogenous ubiquinone-dependent antioxidant system. Deficiency induced an increase in both coenzyme Q9 and Q10 in liver tissue, reaching a maximum between 4 and 7 weeks of deficient diet consumption. Cytochrome b5 reductase polypeptide was also enriched in membranes after 5 weeks of deficient diet consumption. Substantial DT-diaphorase activity was found in deficient, but not in control plasma membranes. Deficient membranes were very sensitive to lipid peroxidation, although a great protection was observed after incubation with NAD(P)H. Our results show that liver cells can boost endogenous ubiquinone-dependent protective mechanisms in response to deficiency in vitamin E and selenium.
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PMID:Protective role of ubiquinone in vitamin E and selenium-deficient plasma membranes. 1041 28

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase that is involved in chemoprotection and can also bioactivate certain antitumor quinones. This review focuses on detoxification reactions catalyzed by NQO1 and its role in antioxidant defense via the generation of antioxidant forms of ubiquinone and vitamin E. Bioactivation reactions catalyzed by NQO1 are also summarized and the development of new antitumor agents for the therapy of solid tumors with marked NQO1 content is reviewed. NQO1 gene regulation and the role of the antioxidant response element and the xenobiotic response element in transcriptional regulation is summarized. An overview of genetic polymorphisms in NQO1 is presented and biological significance for chemoprotection, cancer susceptibility and antitumor drug action is discussed.
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PMID:NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. 1115 36

Environmental pollutants, such as polychlorinated biphenyls (PCBs), may induce drug metabolism and may be substrates for the induced metabolic enzymes. Both processes may lead to oxidative stress. The goal of this study was to determine the influence of polychlorinated biphenyls, selected as inducers and substrates of drug metabolism, on oxidative events within the liver over a 3-week time course. Male and female Sprague-Dawley rats received two ip injections per week of 4-chlorobiphenyl, 2,4,4'-trichlorobiphenyl, 3,4,5-trichlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl (PCB 77), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), or both PCB 77 and 153 (100 micromol/kg/injection) and were euthanized at the end of 1, 2, or 3 weeks. Hepatic cytochrome P450 1A1 (EROD) activity, DT-diaphorase activity, AP-1 DNA-binding activity, conjugated dienes, and alpha-tocopherol (vitamin E) as well as alpha-tocopheryl quinone (oxidized vitamin E) were determined. While the lower chlorinated biphenyls (at these doses and times) showed little or no effect on these oxidative stress parameters, both CYP 1A1 and DT-diaphorase activities were significantly increased in both male and female rats receiving PCB 77, a ligand for the aryl hydrocarbon receptor. In addition, the DNA-binding activity of the transcription factor AP-1 was increased in rats treated with PCB 77 or PCB 153. Within the lipid fraction there was no significant increase observed in conjugated diene concentrations, but there was a significant increase in alpha-tocopheryl quinone upon treatment with all PCBs tested. These data indicate that alpha-tocopheryl quinone may be a sensitive marker for PCB exposure and is possibly increased by a wide range of PCBs.
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PMID:Polychlorinated biphenyl-induced effects on metabolic enzymes, AP-1 binding, vitamin E, and oxidative stress in the rat liver. 1122 84

High affinity for NADH, and low affinity for NADPH, for reduction of endogenous coenzyme Q10 (CoQ10) by pig liver plasma membrane is reported in the present work. CoQ reduction in plasma membrane is carried out, in addition to other mechanisms, by plasma membrane coenzyme Q reductase (PMQR). We show that PMQR-catalyzed reduction of CoQ0 by both NADH and NADPH is accompanied by generation of CoQ0 semiquinone radicals in a superoxide-dependent reaction. In the presence of a water-soluble vitamin E homologue, Trolox, this reduction leads to quenching of the Trolox phenoxyl radicals. The involvement of PMQR versus DT-diaphorase under the conditions of vitamin E and selenium sufficiency and deficiency was evaluated for CoQ reduction by plasma membranes. The data presented here suggest that both nucleotides (NADH and NADPH) can be accountable for CoQ reduction by PMQR on the basis of their physiological concentrations within the cell. The enzyme is primarily responsible for CoQ reduction in plasma membrane under normal (nonoxidative stress-associated) conditions.
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PMID:NADH and NADPH-dependent reduction of coenzyme Q at the plasma membrane. 1122 30

NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two- or four-electron reduction of numerous endogenous and environmental quinones (e.g., the vitamin E alpha-tocopherol quinone, menadione, benzene quinones). In laboratory animals treated with various environmental chemicals, inhibition of NQO1 metabolism has long been known to increase the risk of toxicity or cancer. Currently, there are 22 reported single-nucleotide polymorphisms (SNPs) in the NQO1 gene. Compared with the human consensus (reference, "wild-type") NQO1*1 allele coding for normal NQO1 enzyme and activity, the NQO1*2 allele encodes a nonsynonymous mutation (P187S) that has negligible NQO1 activity. The NQO1*2 allelic frequency ranges between 0.22 (Caucasian) and 0.45 (Asian) in various ethnic populations. A large epidemiologic investigation of a benzene-exposed population has shown that NQO1*2 homozygotes exhibit as much as a 7-fold greater risk of bone marrow toxicity, leading to diseases such as aplastic anemia and leukemia. The extent of the contribution of polymorphisms in other genes involved in the metabolism of benzene and related compounds-such as the P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase (GSTM1, GSTT1), microsomal epoxide hydrolase (EPHX1), and other genes-should also be considered. However, it now seems clear that a lowered or absent NQO1 activity can increase one's risk of bone marrow toxicity, after environmental exposure to benzene and benzene-like compounds. In cancer patients, the NQO1*2 allele appears to be associated with increased risk of chemotherapy-related myeloid leukemia. Many other epidemiological studies, attempting to find an association between the NQO1 polymorphism and one or another human disease, have now begun to appear in the medical literature.
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PMID:NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review. 1188 82

Phenobarbital (PB) is an efficacious hepatic tumor promoter. Although the promoting activity of PB is likely related to altered cell proliferation or apoptosis, the induction of an oxidative stress environment may also be important. PB has been shown to activate the transcription factor nuclear factor-kappaB (NF-kappaB). In this study, we hypothesized that PB-induced NF-kappaB activation can be decreased by dietary vitamin E in rats. Male Sprague-Dawley rats (n = 39) were fed a purified diet with varying levels of dietary vitamin E (10, 50 or 250 mg/kg of dl-alpha-tocopherol acetate) for 28 d, at which time 8 rats per level of dietary vitamin E were fed the same diet with 500 mg/kg PB for 10 d. In the rats fed the low vitamin E diet, PB increased NF-kappaB DNA binding, but it did not affect NF-kappaB activation in rats fed higher levels of vitamin E (50 and 250 mg/kg). Vitamin E may decrease the oxidative stress created by PB by also enhancing other antioxidants; therefore, we also measured hepatic glutathione S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase and NAD(P)H:quinone reductase (DT-diaphorase) activities and glutathione and ascorbic acid concentrations. Increased dietary alpha-tocopherol did not affect the antioxidants and antioxidant enzymes altered by PB treatment. Thus, the effect of alpha-tocopherol acetate on NF-kappaB activation does not appear to be mediated by alterations in the antioxidant system. These results demonstrate that the activation of NF-kappaB, a transcription factor that affects cell proliferation- and apoptosis-related gene expression, can be inhibited by dietary vitamin E.
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PMID:Vitamin E inhibits hepatic NF-kappaB activation in rats administered the hepatic tumor promoter, phenobarbital. 1236 15


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