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

The metabolism, cytotoxicity, and genotoxicity of streptonigrin (SN) w ere determined in two human colon carcinoma cell lines: HT-29 with high NAD(P)H:quinone oxidoreductase (EC 1.6.99.2, DTD) activity and BE with undetectable DTD activity. Dicumarol-sensitive oxidation of NADH was observed with HT-29 cytosol, but not with BE cytosol. Oxygen consumption was also observed using HT-29 cytosol, but was absent with BE cytosol. Dicumarol inhibited oxygen consumption with HT-29 cytosol, but deferoxamine had no effect, suggesting that divalent metal cations were not necessary for efficient auto-oxidation of SN hydroquinone. In cytotoxicity studies, SN was much more toxic to the DTD-rich HT-29 cells than to the DTD-deficient BE cells. Deferoxamine decreased toxicity in both cell lines, implicating hydroxyl radicals produced during Fenton-type reactions as the toxic species. In the genotoxicity assay, SN induced a much higher incidence of DNA strand breaks in HT-29 cells than in BE cells, and deferoxamine protected against DNA strand breaks in both cell lines. Some evidence of DNA repair was also observed in the two cell lines. These results support an important role for DTD in the cytotoxicity of SN in the high DTD HT-29 colon carcinoma cell line.
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PMID:Role of NAD(P)H:quinone oxidoreductase (DT-diaphorase) in cytotoxicity and induction of DNA damage by streptonigrin. 861 1

Inhibition of mitochondrial complex I by 6-hydroxydopamine was studied in brain and liver preparations. NADH-quinone reductase activity of this complex from rat brain was inhibited by 6-hydroxydopamine partially uncompetitively with respect to NADH with a value of Ki 0.051 +/- 0.014 mM. The inhibition patterns for liver NADH-quinone reductase were more complicated than those obtained with the brain enzyme. Desferrioxamine behaved as a 'competitive' activator of complex I from both liver and brain (Ka = 2 mM and 0.02 mM, respectively). It also protected brain complex I against the inhibition by increasing Ki value about 10-fold. Furthermore, in the presence of desferrioxamine the residual activity of enzyme-substrate-inhibitor complex was increased. The data suggest that desferrioxamine does not compete directly with 6-hydroxydopamine for binding to the inhibitory site, but induces a conformation which is unfavorable for the binding of the inhibitor to the protein. The qualitative and quantitative differences between the behavior of the liver and brain enzyme complexes indicate that the assumption that the behavior of liver mitochondria can be used as a model for the situation in brain should be reconsidered.
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PMID:Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine. 969 13

The modulation of the HDL receptor scavenger receptor B1 (SRB1) was evaluated in skin fibroblasts isolated from Rett syndrome (RTT) patients, a rare neurodevelopmental disorder affecting almost exclusively females associated in up to 95% of cases to de novo loss-of-function mutations in the X-chromosome-linked gene encoding the methyl-CpG-binding protein 2 (MeCP2). Patients showed an altered plasma lipid profile, while their skin fibroblasts showed a dramatic reduction in SRB1 (immunogold, Western blot and immunohistochemistry). The decreased SRB1 levels were demonstrated to be the consequence of its binding with 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and its increased ubiquitination. Therefore the loss of SRB1 in RTT cells is a consequence of the chronic oxidative stress status present in RTT. In addition RTT fibroblast presented high intracellular levels of H2O2 and 4HNE protein adducts. This finding was correlated with the constitutive activation of NADPH oxidase (NOX) and was reverted by DPI (NOX inhibitor) or Desferal (Iron chelator) pre-treatment. To confirm the alteration of status redox in RTT cells, the activity of several enzymes involved in protecting the cell from OS was also evaluated. Glutathione peroxidase (GPx), Supeoxide dismutase and Glucose-6-phosphate dehydrogenase (G6PDH) activity were decreased respect to control. These data paralleled with a constitutive activation of NRF2 and elevated gene expression of Heme oxigenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO-1). Of note, when NRF2 pathway was stimulated via exogenous oxidants, RTT fibroblast did not respond as the control cells.
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PMID:Scavenger Receptor B1 oxidative post-translational modifications are responsible for its loss in Rett syndrome. 2646 Dec 80

Neuronal cell death in Huntington's Disease (HD) is associated with the abnormal expansions of a polyglutamine (polyQ) tract in the huntingtin protein (Htt) at the N-terminus that causes the misfolding and aggregation of the mutated protein (mHtt). Autophagy-lysosomal degradation of Htt aggregates may protect the neurons in HD. HD patients eventually manifest parkinsonian-like symptoms, which underlie defects in the dopaminergic system. We hypothesized that dopamine (DA) exacerbates the toxicity in affected neurons by over-inducing an oxidative stress that negatively impinges on the autophagy clearance of mHtt and thus precipitating neuronal cell death. Here we show that the hyper-expression of mutant (>113/150) polyQ Htt is per se toxic to dopaminergic human neuroblastoma SH-SY5Y cells, and that DA exacerbates this toxicity leading to apoptosis and secondary necrosis. DA toxicity is mediated by ROS production (mainly anion superoxide) that elicits a block in the formation of autophagosomes. We found that the pre-incubation with N-Acetyl-l-Cysteine (a quinone reductase inducer) or Deferoxamine (an iron chelator) prevents the generation of ROS, restores the autophagy degradation of mHtt and preserves the cell viability in SH-SY5Y cells expressing the polyQ Htt and exposed to DA. The present findings suggest that DA-induced impairment of autophagy underlies the parkinsonism in HD patients. Our data provide a mechanistic explanation of the DA toxicity in dopaminergic neurons expressing the mHtt and support the use of anti-oxidative stress therapeutics to restore protective autophagy in order to slow down the neurodegeneration in HD patients.
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PMID:Dopamine exacerbates mutant Huntingtin toxicity via oxidative-mediated inhibition of autophagy in SH-SY5Y neuroblastoma cells: Beneficial effects of anti-oxidant therapeutics. 2784 Jan 25