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)

Protocatechuic acid, a naturally occurring plant polyphenol, was shown to decrease the mutagenicity and/or carcinogenicity of several amine derivatives and polycyclic aromatic hydrocarbons in rodents. In this study the effect of protocatechuic acid on murine cytochrome P450 and phase II enzymes was evaluated. The activities of EROD, MROD, PROD, PNPH, GST, UDPGT and NQO1 were measured in the liver and kidney microsomes of female Swiss mice treated intraperitoneally (i.p.) with protocatechuic acid in the dose range of 80-800 mg/kg. At the highest doses, protocatechuic acid decreased the activities of EROD and MROD by approximately 20-30% in mouse liver and kidney, while the activity of renal PNPH was reduced by 28%. Moreover, Western blot analysis with CYP1A1/1A2 and CYP2E1-specific antibodies showed the same effect on the levels of hepatic CYP1A1/1A2 and CYP2E1 proteins. This simple phenol affected also the phase II enzymes. The activity of GST was elevated in both tissues of the animals treated with protocatechuic acid at the dose of 80 mg/kg. The inhibition of hepatic NQO1 was the most striking effect. The effect was dose dependent and almost 70% inhibition was observed after treatment with protocatechuic acid at the dose of 800 mg/kg. In contrast to the liver, the renal NQO1 was not affected. These results indicate that protocatechuic acid, as other phenolic acids, beside of scavenging active metabolites of chemical carcinogens, can change their metabolism by modulating the enzymes involved in xenobiotics activation and/or detoxification pathways, but this effect depends on tissue.
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PMID:Modulation of cytochrome P450 and phase II enzymes by protocatechuic acid in mouse liver and kidney. 1613 15

TCDD was assessed as a biological response modifier for increasing MMC cytotoxicity through aryl hydrocarbon receptor (AhR) activation and increasing levels of bioreductive enzymes. Human MCF-7 cells were exposed to TCDD, MMC and combinations thereof under aerobic or hypoxic conditions. Cytotoxicity, enzyme activities (NQO1, XO, XDH, CYPR, CYP1A, GST and UGT) and intracellular reactive oxygen species (ROS) were subsequently measured. Under aerobic conditions, TCDD alone had no significant toxicity but combinations of TCDD and MMC significantly increased cell death. LD50 values were: MMC alone, 0.89 +/- 0.04 microM; TCDD co-treatment, 0.26 +/- 0.007 microM (P = 0.008 vs. MMC alone) and TCDD pre-treatment, 0.04 +/- 0.01 microM (P = 0.003 vs. MMC alone). Under hypoxia, TCDD itself caused significant cell death, likely due to increased ROS, but no combinations of MMC/TCDD altered the LD50 of MMC. Significant changes in enzyme activities were caused by TCDD under aerobic but not hypoxic conditions while MMC decreased the activity of its activating enzymes regardless of oxygen tension. Greater toxicity of MMC/TCDD combinations in aerobic culture, were most likely mediated by increased levels of bioreductive enzymes caused through AhR activation. Data presented herein also demonstrate that low oxygen tension decreases AhR activation and signaling and increases the inherent toxicity of TCDD.
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PMID:TCDD as a biological response modifier for Mitomycin C: oxygen tension affects enzyme activation, reactive oxygen species and cell death. 1622 70

We investigated the cytoprotective mechanisms of flunarizine in cisplatin-induced death of auditory cells. Concomitant with an increase in viability, treatment with flunarizine resulted in a marked dissociation of Nrf2/Keap1 and subsequent intranuclear translocation of Nrf2, which was mediated by PI3K-Akt signaling. Overexpression of Nrf2 protected cells from cisplatin along with transcriptional activation of ARE to generate heme oxygenase-1 (HO-1). Pretreatment with flunarizine predominantly increased the transcriptional activity of HO-1 among Nrf2-driven transcripts, including HO-1, NQO1, GCLC, GCLM, GST micro-1, and GSTA4. Furthermore, both pharmacological inhibition and siRNA transfection of HO-1 completely abolished the flunarizine-mediated protection of HEI-OC1 cells and the primary rat (P2) organ of Corti explants from cisplatin. These results suggest that Nrf2-driven transcriptional activation of ARE through PI3K-Akt signaling augments the generation of HO-1, which may be a critically important determinant in cellular response toward cisplatin and the cytoprotective effect of flunarizine against cisplatin.
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PMID:Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin. 1648 34

The levels of the enzymes, glutathione S-transferase, catalase, NAD(P)H-cytochrome c reductases, and DT-diaphorase were determined and compared in the tissues of three invertebrates commonly used in monitoring environmental quality: a freshwater mussel, Dreissena polymorpha, the earthworm Allolobophora chlorotica and the fourth instar of Chironomus riparius. It was found that the activities of GST, catalase, and NAD(P)-cytochrome c reductases were comparable in A. chlorotica and C. riparius, whereas comparatively a higher GST and a lower catalase activity was determined in the mussel tissues. DT-diaphorase was not detectable in A. chlorotica and the C. riparius larvae tissues, whereas this enzyme is present in the gills and the rest of soft mussel tissues (soft mussel tissues minus gills). It is suggested that the relatively low catalase activity observed in the tissues of the latter organism might be compensated by the presence of the antixidant role of DT-diaphorase. In addition, the inducibility of DT-diaphorase in D. polymorpha, by butylated hydroxyanisole (BHA) and lead (Pb) was investigated. Despite the bioaccumulation of both BHA (5.2+/-0.14 microgg(-1) wet weight) and Pb (233.7+/-0.95 mgkg(-1) dry weight) in the soft mussel tissues, the mussel DT-diaphorase was not induced. Although the activity of NADPH-cytochrome c (P-450) reductase was also not affected by these reagents, its activity was 2-fold higher in the gills than the rest of soft mussel tissues.
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PMID:Comparison of key enzymes in the zebra mussel, Dreissena polymorpha, the earthworm Allolobophora chlorotica and Chironomus riparius larvae. 1705 54

Cells respond to the shift of intracellular environment toward pro-oxidant conditions by activating the transcription of numerous "antioxidant" genes. This response is based on the activation of the Nrf2 transcription factor, which transactivates the genes containing in their promoters the antioxidant response cis-elements (AREs). If the oxidative stress provokes DNA damage, a second response of the cell takes place, based on the activation of p53, which induces cell cycle arrest and/or apoptosis. Here we have explored the cross-talk between these two regulatory mechanisms. The results show that p53 counteracts the Nrf2-induced transcription of three ARE-containing promoters of the x-CT, NQO1, and GST-alpha1 genes. Endogenous transcripts of these antioxidant genes accumulate as a consequence of Nrf2 overexpression or exposure to electrophile diethylmaleate, but these effects are again blocked by p53 overexpression or endogenous p53 activation. Chromatin immunoprecipitation experiments support the hypothesis that this p53-dependent trans-repression is due to the direct interaction of p53 with the ARE-containing promoters. Considering that p53-induced apoptosis requires an accumulation of reactive oxygen species, this negative control on the Nrf2 transactivation appears to be aimed to prevent the generation of a strong anti-oxidant intracellular environment that could hinder the induction of apoptosis.
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PMID:p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. 1707 87

Functional polymorphisms in the genes encoding detoxification enzymes could modify the response to treatment in acute myeloid leukemia and therefore affect the final clinical outcome. In the present study, we genotyped 153 patients diagnosed with de novo acute myeloid leukemia (AML) to clarify the influence of the genetic polymorphisms CYP1A1*2A, CYP3A4*1B, CYP2E1*5B, del{GSTT1}, del{GSTM1}, and NQO1*2 on disease outcome. The del{GSTM1} showed a higher frequency in females (62%) than in males (41%) (P=0.01). The number of functional NQO1 alleles influenced the response to induction therapy; 81% (55/68) NQO1-negative patients, 69% (28/41) heterozygous patients, and 27% (2/7) homozygous patients achieved complete remission (CR) (P=0.04). The presence of GST deletions was associated with a lower probability of disease-free survival (DFS) and this effect was more relevant in male patients. Males with del{GSTM1} showed a 28% DFS versus 57% DFS for undeleted GSTM1 (P=0.04). Similarly, males with undeleted GSTM1 and GSTT1 showed a 64% DFS versus 34% DFS for males with at least one GST deletion (P=0.05). This study suggests that the NQO1*2 polymorphism is relevant to the patient's response to induction therapy and that GST deletions influence treatment outcome after chemotherapy, especially in male patients.
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PMID:The GST deletions and NQO1*2 polymorphism confers interindividual variability of response to treatment in patients with acute myeloid leukemia. 1711 47

In epidemiology and human supplementation studies, as well as many animal models, selenium has shown antitumorigenic activity. The mechanism of action, however, has not been satisfactorily resolved. Selenium supplementation affects many enzymes in addition to those where selenocysteine is an essential component. Such enzymes include cytoprotective detoxifying enzymes, and the regulation of these enzymes by a set of 2-substituted selenazolidine-4(R)-carboxylic acids (SCAs) has been investigated. Following seven consecutive daily doses of these prodrugs of L-selenocysteine, changes in hepatic enzyme activities and/or mRNA levels of glutathione transferase (GST), microsomal epoxide hydrolase (mEH), NAD(P)H-quinone oxidoreductase (NQO), UDP-glucuronosyltransferase (UGT), glutathione peroxidase (GPx), and thioredoxin reductase (TR) have been observed. Among the enzymes examined, UGTs and GPx were found to be the least affected. Among the compounds, 2-oxoSCA produced the most changes and 2-phenylSCA produced the least, none. For no two compounds was the pattern of changes identical, and for a single compound, few changes were reproduced in common by the two routes of administration investigated. In general, more changes were elicited following intraperitoneal (i.p.) administration than with the intragastric (i.g.) route. This dominance was typified by 2-butylSCA and 2-cyclohexylSCA where enzyme activity elevations (TR and mEH with both, NQO with 2-butylSCA) were seen only with the i.p. route. With 2-oxoSCA, however, GST, TR, and NQO activities were found to be elevated independent of route. Only with GST (both routes) and TR (i.p. route), elevations in mRNAs accompanied the 2-oxoSCA elicited elevations of activities at the time of sacrifice. For some enzymes, most notably mEH with compounds administered i.p., elevations in mRNAs were not manifest as increased enzyme activity. Thus, although constituting a closely related series of compounds, each 2-substituted SCA produced its own unique pattern of changes, and for most members, changes were predominant following i.p. administration.
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PMID:Hepatic chemoprotective enzyme responses to 2-substituted selenazolidine-4(R)-carboxylic acids. 1716 88

In this study, zebra mussels, D. polymorpha, were exposed to extracts of sediments obtained from two sites, a contaminated lake (Ketelmeer, Km) and a relatively clean lake (Drontenmeer, Dm). The main objective of this work was to investigate whether six selected biomarkers could discriminate between the two sediments. The selected biomarkers included phase I enzymes such as DT-diaphorase, NADPH-cytochrome c reductase, NADH-cytochrome c reductase, a phase II enzyme (glutathione S-transferase, GST), an antioxidant enzyme, catalase, and the total glutathione, reduced (GSH) and oxidized (GSSG). After a short (24 h) and a long-term (7 days) exposure, the levels of these biomarkers were measured in gills and the rest of soft mussel tissues (soft mussel tissue minus gills) and compared with control values. A decrease of GST level by 20% (P = 0.004) and a 4-fold decrease of total glutathione concentration relative to the control, were observed in the gills of mussels exposed to the more contaminated Km extract. No significant differences in the GST activities were observed in the gills of control and Dm extract-treated mussels (P = 0.23). Although the levels of catalase and NADH-cytochrome c reductase were, in the short-term exposure, unaffected, both activities were, in the long-term exposure, reduced in the gills of the mussels exposed to the contaminated Km extract, compared with control values, by 43% and 20%, respectively. The activities of DT-diaphorase and NADPH-cytochrome c reductase remained unaffected in all exposure conditions. However, the level of NADPH-cytochrome c reductase was found higher in gills than in the rest of soft mussel tissues. This difference in the ratio of the two reductases between the two tissues could account for the observed differential responses of the biomarkers.
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PMID:Differential responses of biomarkers in tissues of a freshwater mussel, Dreissena polymorpha, to the exposure of sediment extracts with different levels of contamination. 1718 75

In our previous study, we demonstrated that the initial hepatic injury caused by bromobenzene (BB) was no longer detected in rats despite subsequent dosing, indicating that the liver acquired resistance to BB-induced hepatotoxicity. In this experiment, microarray analysis was conducted to characterize this resistance. The liver samples for the analysis utilized were obtained from previous experiments where F344 rats were treated intraperitoneally with BB (150 mg/kg). At 24 hr post-dose, hepatic injury was confirmed by monitoring the AST values and then the rats were maintained at the same dosing regimen for an additional 8 days. The gene expression profiles of the BB-treated rat livers were compared with a vehicle-treated group by Affymetrix RG_U34A arrays. As results, a decreased expression level of CYP3A9 and an increased expression level of GST Yc2 and glutathione peroxidase (GPX) were detected. These changes indicated suppression of the phase I reaction and induction of the phase II reaction (glutathione conjugation). Increased expression levels of epoxide hydrolase (EH) and NAD(P)H:quinone oxidoreductase (NQO1) also suggested the involvement of EH- and NQO1-mediated hydrolysis other than glutathione conjugation with resistance in the phase II reaction. Moreover, an increased expression level of abcc3 (multidrug resistance protein 3; Mrp3) was significantly noted. Based on the present findings, it was suggested that Mrp3 in the phase III reaction (drug elimination) contributed to the resistance to BB hepatotoxicity in addition to the suppression of the phase I reaction (metabolic activation) and the induction of the phase II reaction (detoxification). Among them, the factors which contributed most were considered to be the increased GST Yc2 and Mrp3, based on the degree of the gene expression changes.
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PMID:Characterization of resistance to bromobenzene-induced hepatotoxicity by microarray. 1753 37

In rat liver, in addition to their intrinsic transferase activity, alpha-class GSTs have Se-independent glutathione peroxidase activity toward fatty acid hydroperoxides, cumene hydroperoxide and phospholipids hydroperoxides but not toward H(2)O(2.) We have previously shown that hepatic GST activity by these isoenzymes is significantly increased 24h after cadmium or manganese administration (Casalino et al., 2004). Here it is reported that Se-independent glutathione peroxidase activity by alpha-class GSTs is also stimulated in the liver of intoxicated rats. The stimulation is associated with a higher level of alpha-class GST proteins, whose induction is blocked by actinomycin D co-administration. The observed Se-independent glutathione peroxidase activity is due to alpha-class GST isoenzymes, as indicated by the studies with diethyldithiocarbamate which, at any concentration, equally inhibits both GST and Se-independent glutathione peroxidase and is an uncompetitive inhibitor of both enzymes. As for liver Se-GSPx, it is not at all affected under these toxic conditions. For comparison, we have evaluated the status of another important antioxidant enzyme, NAD(P)H:quinone reductase, 24h after cadmium or manganese administration. NQO1 too results strongly stimulated in the liver of the intoxicated rats. In these animals, a higher expression of Nrf2 protein is observed, actively translocated from the cytoplasm to the nucleus. The results with the transcription inhibitor, actinomycin D, and the effects on Nrf2 protein are the first clear indication that acute manganese intoxication, similarly to that of cadmium and other heavy metals, increases both the hepatic level of Nrf2 and its transfer from the cytoplasm to the nucleus where it actively regulates the induction of phase II enzymes.
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PMID:The Nrf2 transcription factor contributes to the induction of alpha-class GST isoenzymes in liver of acute cadmium or manganese intoxicated rats: comparison with the toxic effect on NAD(P)H:quinone reductase. 1757 73


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