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)

Resveratrol, a polyphenolic compound found in grape skin and peanuts has been shown to prevent many diseases including cardiovascular diseases and cancer. To better understand resveratrol's potential in vivo toxicity, we studied the dose response using cDNA stress arrays coupled with drug metabolizing enzymatic (DME) assays to investigate the expression of stress-responsive genes and Phase I and II detoxifying enzymes in rat livers. Male and female CD rats were treated with high doses of resveratrol (0.3, 1.0 and 3.0 gm/kg/day) for a period of 28 days. Total RNA from rat liver was reverse-transcribed using gene-specific primers and hybridized to stress-related cDNA arrays. Among female rats, Phase I DME genes were repressed at 0.3 and 1.0 gm/kg/day doses, while genes such as manganese superoxide dismutase, cytochrome P450 reductase, quinone oxidoreductase and thiosulfate sulfurtransferase demonstrated a dose-dependent increase in gene expression. The modulation of these liver genes may implicate the potential toxicity as observed among the rats at the highest dose level of resveratrol. Real-Time PCR was conducted on some of the Phase II DME genes and anti-oxidant genes to validate the cDNA array data. The gene expression from real-time PCR demonstrated good correlation with the cDNA array data. UGT1A genes were amongst the most robustly induced especially at the high doses of resveratrol. We next performed Phase I and Phase II enzymatic assays on cytochrome P450 2E1 (CYP2E1), cytochrome P450 1A1 (CYP1A1), NAD(P)H:quinone oxidoreductase (NQO1), glutathione S-transferase (GST) and UDP-glucuronosyl transferase (UGT). Induction of Phase II detoxifying enzymes was most pronounced at the highest dose of resveratrol. CYP1A1 activity demonstrated a decreasing trend among the 3 dose groups and CYP2E1 activity increased marginally among female rats over controls. In summary, at lower doses of resveratrol there are few significant changes in gene expression whereas the modulation of liver genes at the high dose of resveratrol may implicate the potential toxicity observed.
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PMID:Toxicogenomics of resveratrol in rat liver. 1574 24

Ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines, is a very labile protein. ODC is a homodimeric enzyme that undergoes ubiquitin-independent proteasomal degradation via direct interaction with antizyme, a polyamine-induced protein. Binding of antizyme promotes the dissociation of ODC homodimers and marks ODC for degradation by the 26S proteasomes. We describe here an alternative pathway for ODC degradation that is regulated by NAD(P)H quinone oxidoreductase 1 (NQO1). We show that NQO1 binds and stabilizes ODC. Dicoumarol, an inhibitor of NQO1, dissociates ODC-NQO1 interaction and enhances ubiquitin-independent ODC proteasomal degradation. We further show that dicoumarol sensitizes ODC monomers to proteasomal degradation in an antizyme-independent manner. This process of NQO1-regulated ODC degradation was recapitulated in vitro by using purified 20S proteasomes. Finally, we show that the regulation of ODC stability by NQO1 is especially prominent under oxidative stress. Our findings assign to NQO1 a role in regulating ubiquitin-independent degradation of ODC by the 20S proteasomes.
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PMID:20S proteasomal degradation of ornithine decarboxylase is regulated by NQO1. 1574 15

The Nrf2-Keap1 system coordinately regulates cytoprotective gene expression via the antioxidant responsive element (ARE). The expression of several ARE-regulated genes was found to be up-regulated in endothelial cells by laminar shear stress, suggesting that Nrf2 contributes to the anti-atherosclerosis response via the ARE. To gain further insight into the roles that Nrf2 plays in the development of atherosclerosis, we examined how Nrf2 regulates gene expression in response to anti-atherogenic laminar flow (L-flow) or pro-atherogenic oscillatory flow (O-flow). Exposure of human aortic endothelial cells (HAECs) to L-flow, but not to O-flow, induced the expression of cytoprotective genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1) by 5-fold and heme oxygenase-1 by 8-fold. The critical contribution of Nrf2 to the expression induced by L-flow was ascertained in siRNA-mediated knock-down experiments. Two cyclooxygenase-2 (COX-2) specific inhibitors attenuated Nrf2 nuclear accumulation in the acute phase of L-flow exposure. A downstream product of COX-2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), activated the Nrf2 regulatory pathway in HAECs through binding to the cysteines of Keap1. These results demonstrate that 15d-PGJ2 is essential for L-flow to activate Nrf2 and induce anti-atherosclerotic gene expression. Whereas both L-flow and O-flow induced the nuclear accumulation of Nrf2 to comparable levels, chromatin immunoprecipitation analysis revealed that Nrf2 binding to the NQO1 ARE was significantly diminished in the case of O-flow compared with that of L-flow. These results suggest that O-flow inhibits Nrf2 activity at the DNA binding step, thereby suppressing athero-protective gene expression and hence predisposing the blood vessels to the formation of atherosclerosis.
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PMID:Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. 1591 55

Tanshinone IIA, a major component extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge, is known to exhibit potent cytotoxicity against various human carcinoma cells in vitro. However, the mechanism by which tanshinone IIA produces this anti-tumor effect remains unknown. Since anti-neovascularization has generally been regarded as an effective strategy for anti-cancer therapy, we decided to investigate the mechanism underlying tanshinone IIA-mediated death of human endothelial cells. In this study, we demonstrate that tanshinone IIA elicits human endothelial cell death independent of oxidative stress. These events are partially calcium-dependent and actually dependent upon NAD(P)H: quinone oxidoreductase (NQO1) activity. Tanshinone IIA induces an increase in intracellular calcium, which triggers the release of cytochrome c, thus causing loss of the mitochondrial membrane potential (MMP), resulting in the subsequent activation of caspases. Blocking the induction of Ca2+ perturbation with BAPTA-AM partially rescued cells from tanshinone IIA-induced cytotoxicity. Additionally, blocking NQO1 activity with dicoumoral or inhibiting caspase activities with the general caspase inhibitor, z-VAD-fmk, prevented cell death induced by tanshinone IIA. Therefore, our results imply that tanshinone IIA-mediated cytotoxicity against human endothelial cells may occur through activation of NQO1, which induces a calcium imbalance and mitochondrial dysfunction, thus stimulating caspase activity.
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PMID:Tanshinone IIA isolated from Salvia miltiorrhiza elicits the cell death of human endothelial cells. 1591 98

This report is part of an extensive biomarker study conducted in a Chinese occupational population with benzene exposures ranging from 0.06 to 122 ppm (median exposure of 3.2 ppm). All urinary benzene metabolites measured in this study were significantly elevated after exposure to benzene at or above 5 ppm. Among these metabolites, however, only S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) showed a significant exposure-response trend over the exposure range from 0 to 1 ppm (for S-PMA, p<0.0001 and for t,t-MA, p=0.006). For benzene exposure monitoring, both S-PMA and t,t-MA were judged to be good and sensitive markers, which detected benzene exposure at around 0.1 and 1 ppm, respectively. Polymorphisms of the metabolic genes, including CYP2E1, quinone oxidoreductase (NQO1), GSTT1, and myeloperoxidase (MPO), were identified and did not show significant effects on the formation of metabolites, except GSTT1 on S-PMA. The production rate of S-PMA from benzene in exposed workers with GSTT1 null alleles (24.72+/-32.48 microg/g creatinine/ppm benzene) was significantly lower than that in subjects with the wild type of GSTT1 (59.84+/-47.66 microg/g creatinine/ppm benzene, p<0.0001). Further regression analysis of S-PMA production rate on GSTT1 genotype with adjustment of sex, age, benzene exposure, and cotinine levels indicated that the genotype of GSTT1 plays a critical role in determining the inter-individual variations of S-PMA formation from benzene exposure. Therefore, the individual genotype of GSTT1 needs to be identified and considered while using S-PMA as a marker to estimate the personal exposure levels of benzene in future population studies.
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PMID:Biomarkers of benzene: urinary metabolites in relation to individual genotype and personal exposure. 1593 3

At least two types of quinone reductases are present in plants: (1) the zeta-crystallin-like quinone reductases (QR1, EC 1.6.5.5) that catalyze the univalent reduction of quinones to semiquinone radicals, and (2) the DT-diaphorase-like quinone reductases (QR2, EC 1.6.99.2) that catalyze the divalent reduction of quinones to hydroquinones. QR2s protect cells from oxidative stress by making the quinones available for conjugation, thereby releasing them from the superoxide-generating one electron redox cycling, catalyzed by QR1s. Two genes, putatively encoding a QR1 and a QR2, respectively, were isolated from an expressed sequence tag collection derived from the epidermis of a diploid wheat Triticum monococcum L. 24 h after inoculation with the powdery mildew fungus Blumeria graminis (DC) EO Speer f. sp. tritici Em. Marchal. Northern analysis and tissue-specific RT-PCR showed that TmQR1 was repressed while TmQR2 was induced in the epidermis during powdery mildew infection. Heterologous expression of TmQR2 in Escherichia coli confirmed that the gene encoded a functional, dicumarol-inhibitable QR2 that could use either NADH or NADPH as an electron donor. The localization of dicumarol-inhibitable QR2 activity around powdery mildew infection sites was accomplished using a histochemical technique, based on tetrazolium dye reduction.
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PMID:Differential regulation of wheat quinone reductases in response to powdery mildew infection. 1607 99

Protein degradation is a key cellular process involved in almost every aspect of the living cell. The current prevailing concept is that proteins are stable unless marked by poly-ubiquitination for degradation by the proteasomes. Studies on the tumor suppressor p53 have indeed demonstrated that poly-ubiquitination of p53 by different E3 ubiquin ligases targets p53 for degradation by the 26S proteasomes. Recent findings suggest that p53 also undergoes ubiquitin-independent degradation by the 20S proteasomes and that this process is regulated by NAD(P)H quinone oxidoreductase 1 (NQO1) together with NADH. This "degradation by default" mechanism sheds new light on our understanding of p53 degradation and possibly on protein degradation in general and may establish a new principle in protein stability with wide physiological implications.
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PMID:p53 proteasomal degradation: poly-ubiquitination is not the whole story. 1608 97

Monofunctional inducers (MIs) enhance phase 2 enzymes such as nicotinamide-adenine-dinucleotide-phosphate [NAD(P)H] quinone oxidoreductase (NQO1) without modifying oxidation enzymes. The induction of these protective enzymes appears to be mediated by genetic regulatory elements in their promoter regions known as the antioxidant response element (ARE). The aim of this study was to identify, through an in vitro study, which of the 30 fruits and vegetables commonly consumed in Catalonia, Spain, contain MIs of NQO1. We assayed the capacity of extracts of these fruits and vegetables to induce NQO1 [by more than 1.5-fold: ratio of induction (cells treated/control) >1.5, 8-mg/ml dose] in two murine hepatoma cell lines: Hepa 1c1c7 and BPrC1, a modified cell line that possesses a nonfunctional aryl hydrocarbon receptor nuclear translocator system and is thus nonresponsive to bifunctional inducers. We also used a third cell line, papiloma (PE) murine keratinocytes, a stably transfected cell line with an ARE-luc+ plasmid (AREPE cell line) for verifying induction through the ARE with a simple luminescence screening assay. Broccoli (Hepa 1c1c7, ratio=5.5; BPrC1, ratio=2.3), calcot (Allium cepa L.) (Hepa 1c1c7, ratio=4.7; BPrC1, ratio=.5), green onion (Hepa 1c1c7, ratio=4.6; BPrC1, ratio=2), green cabbage (Hepa 1c1c7, ratio=3.6; BPrC1, ratio=2.7), purple cabbage (Hepa 1c1c7, ratio=3.4; BPrC1, ratio=2), and black cabbage (Hepa 1c1c7, ratio=3; BPrC1, ratio=3) were active NQO1 inducers in both murine hepatoma cell lines. Extracts from broccoli (ratio=3.5), calcot (ratio=4.8), cauliflower (ratio=4.2), cabbage (ratio=2.2), green onion (ratio=3.2), green cabbage (ratio=3.6), black cabbage (ratio=4.5), and purple cabbage (ratio=3.7) were confirmed to contain MIs in the AREPE cell line. These results are very similar to those described for vegetables consumed in the United States, with the exception of calcot, which is common in Catalonia but is not grown or consumed widely in the United States.
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PMID:Induction of NAD(P)H quinone oxidoreductase by vegetables widely consumed in Catalonia, Spain. 1609 Oct 4

Far-red illumination of plant leaves for a few seconds induces a delayed luminescence rise, or afterglow, that can be measured with the thermoluminescence technique as a sharp band peaking at around 40-45 degrees C. The afterglow band is attributable to a heat-induced electron flow from the stroma to the plastoquinone pool and the PSII centers. Using various Arabidopsis and tobacco mutants, we show here that the electron fluxes reflected by the afterglow luminescence follow the pathways of cyclic electron transport around PSI. In tobacco, the afterglow signal relied mainly on the ferredoxin-quinone oxidoreductase (FQR) activity while the predominant pathway responsible for the afterglow in Arabidopsis involved the NAD(P)H dehydrogenase (NDH) complex. The peak temperature T(m) of the afterglow band varied markedly with the light conditions prevailing before the TL measurements, from around 30 degrees C to 45 degrees C in Arabidopsis. These photoinduced changes in Tm followed the same kinetics and responded to the same light stimuli as the state 1-state 2 transitions. PSII-exciting light (leading to state 2) induced a downward shift while preillumination with far-red light (inducing state 1) caused an upward shift. However, the light-induced downshift was strongly inhibited in NDH-deficient Arabidopsis mutants and the upward shift was cancelled in plants durably acclimated to high light, which can perform normal state transitions. Taken together, our results suggest that the peak temperature of the afterglow band is indicative of regulatory processes affecting electron donation to the PQ pool which could involve phosphorylation of NDH. The afterglow thermoluminescence band provides a new and simple tool to investigate the cyclic electron transfer pathways and to study their regulation in vivo.
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PMID:Probing the FQR and NDH activities involved in cyclic electron transport around Photosystem I by the 'afterglow' luminescence. 1613 41

Intracellular proteolysis plays an important role in regulating fundamental cellular processes such as cell cycle, immune and inflammation responses, development, differentiation, and transformation. The ubiquitin-proteasome system accounts for the degradation of the majority of cellular short-lived proteins. This system involves the conjugation of multiple ubiquitin residues to the target protein and its recognition by the 26S proteasome through the poly-ubiquitin chain. Studies on the degradation of ornithine decarboxylase (ODC) demonstrated that poly-ubiquitin is not the only signal recognized by the 26S proteasome. The recognition of ODC by the 26S proteasome is mediated by interaction with a polyamine-induced protein termed, antizyme (Az). While the degradation of ODC is ubiquitin-independent, the degradation of its regulator Az, and of antizyme-inhibitor (AzI), an ODC homologous protein that regulates Az availability, are ubiquitin dependent. Interestingly, ODC undergoes another type of ubiquitin-independent degradation by the 20S proteasome that is regulated by NAD(P)H quinone oxidoreductase 1 (NQO1). Considering the prevalence of the ubiquitin system in the process of cellular protein degradation it is rather remarkable that a key cellular enzyme is subjected to two different proteolytic pathways that are different from the ubiquitin dependent one. This exceptional behavior of ODC provides us with valuable insights regarding protein degradation in general.
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PMID:Mechanisms of protein degradation: an odyssey with ODC. 1620 22


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