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)

Effect of vanadium on hepatic xenobiotic biotransformation in rats exposed to diethylnitrosamine (DENA, 200 mg/kg body weight, intraperitoneally) was investigated to elucidate a possible mechanism of vanadium mediated prevention of chemical carcinogenesis. Vanadium supplementation (0.5 ppm ad libitum with drinking water), at different phases before and after DENA treatment, significantly modulated the decrease in contents of total cytochrome P-450, cytochrome b5, activity of nicotinamide adenine dinucleotide phosphate (NADPH), (reduced form) cytochrome reductase, and uridine diphospho-glucuronyl transferase (UDPGT) in microsomal fractions of whole liver, hyperplastic nodules (HNs) and non nodular surrounding parenchyma (NNSP) as induced by DENA, 20 weeks following its administration. Supplementary vanadium had also substantial influence on the activities of cytosolic enzymes, like, uridine diphospho (UDP)-glucose dehydrogenase and NAD(P)H: quinone oxidoreductase (DT-diaphorase) in the concerned tissue which were observed to be remarkably decreased as a result of DENA treatment in comparison to that of the control counterparts. However, vanadium was found to have little or no effect on the lowering ofaryl hydrocarbon hydroxylase (AHH) activity by DENA administration. On the basis of significant modulation of DENA induced alterations in cytosolic and microsomal enzyme activity it can be presumed that the chemoprotective effect of vanadium might be mediated through elevation of phase II conjugating enzymes which in turn, lead to a move and shift of metabolic profile that reduces the intracellular concentration of carcinogen derived reactive intermediates.
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PMID:Differential modulation of xenobiotic metabolizing enzymes by vanadium during diethylnitrosamine-induced hepatocarcinogenesis in Sprague-Dawley rats. 1098 72

Genetically obese Zucker rats exhibit symptoms similar to those of obese patients with insulin-resistance or Type II diabetes; therefore, they have been used as a genetic model to study obesity, as well as a pharmacological model for the discovery of new drugs for the treatment of Type II diabetes and hyperlipidemia. In the present study, we compared the pharmacokinetics of two novel peroxisome proliferator-activated receptor (PPAR) agonists, MRL-I [(2R)-7-[3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy]-2-ethyl-3,4-dihydro-2H-benzopyran-2-carboxylic acid] and MRL-II [(2R)-7-[3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy]-3,4-dihydro-2-methyl-2H-benzopyran-2-carboxylic acid], in obese Zucker and lean Sprague-Dawley rats following a single intravenous administration. The plasma clearance of both MRL-I and MRL-II was significantly lower in obese Zucker rats (4- and 2-fold, respectively) compared with Sprague-Dawley rats, but without any significant change in the volume of distribution, which resulted in a dramatic increase in the half-life (7- and 3-fold, respectively). The reversible in vitro plasma protein binding of [(14)C]MRL-I and [(14)C]MRL-II was comparable in the two strains, approximately 96% bound. The expression levels of uridine diphosphate-glucuronosyltransferases 1A1, 1A6, 2B1, and CYP2C11 and 3A1 mRNA in liver were lower (30-50%) in Zucker compared with Sprague-Dawley rats, as were the liver glutathione S-transferases (70%), quinone reductase (30%), organic anion-transporting protein 2 (80%), and multidrug resistance-associated protein 2 (Mrp2) (50%) mRNA levels. However, Mrp3 mRNA levels were similar in both strains. Consistent with these observations, the intrinsic clearance (CL(int)), calculated from the V(max)/K(m) of glucuronidation of [(14)C]MRL-I and [(14)C]MRL-II in liver microsomes, was approximately 2-fold lower in obese Zucker rats; the K(m) values were comparable in the two strains for both compounds. In conclusion, differences in the pharmacokinetics of two novel PPAR agonists, both cleared, predominantly, by conjugation, were evident in genetically obese Zucker rats compared with Sprague-Dawley rats. These differences were consistent with changes in the mRNA levels of hepatic drug-metabolizing enzymes and transporters. This information should be considered when comparing pharmacokinetic and efficacious doses in the obese Zucker rats, used as a pharmacological model, with those in Sprague-Dawley rats, which are used widely for drug metabolism and toxicology studies.
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PMID:Differences in the pharmacokinetics of peroxisome proliferator-activated receptor agonists in genetically obese Zucker and sprague-dawley rats: implications of decreased glucuronidation in obese Zucker rats. 1531 30

The effect of 5-OH-1,4-naphthoquinone (5OH-NQ), a known inhibitor of germination and growth and an inducer of oxidative stress, on seeds from Norway spruce (Picea abies) during germination was studied. 5OH-NQ was activated by homogenate from seeds to reactive species that reduce oxygen to superoxide radicals in vitro. Increasing concentrations of 5OH-NQ increased lipid peroxidation during this activation. Small effects of 5OH-NQ on germination of seeds were observed at concentrations up to 200 mum. However, higher concentrations, e.g. 500 and 1000 mum, exerted more pronounced effects on seeds. These results suggest that the effect of 5OH-NQ was a delay rather than an inhibition of germination. However, the effect of 5OH-NQ on postgerminative growth was more potent than that on germination, and higher concentrations inhibited growth >97%. These results suggest that the seeds have a very effective defense system against quinone and reactive oxygen species, since the small effects of 5OH-NQ on germination and postgermination at concentrations up to 200 mum can be explained by the formation of a metabolite of 5OH-NQ that is not as reactive with oxygen as the original quinone. The 5OH-NQ metabolite collected during germination experiments showed differences in its absorption spectrum in comparison with 5OH-NQ, which suggest changes in structure. This metabolite was reduced by quinone reductase, but reduction of oxygen to superoxide radicals was not detected during its activation with homogenate from seeds. This metabolite may arise via a conjugation reaction, since the addition of 500 mum uridine 5'-diphosphoglucuronic acid or 3'-phosphoadenosine-5'-phosphosulfate to the incubation mixture during activation of this metabolite by homogenate from seeds in vitro inhibited reduction of oxygen to superoxide radicals by 50 and 64%, respectively. The constitutive levels of superoxide dismutase and catalase were sufficient to prevent oxygen toxicity during activation of 5OH-NQ, since these enzymes were not induced when the seeds were treated with 200 mum 5OH-NQ.
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PMID:The Effect of 5OH-1,4-Naphthoquinone on Norway Spruce Seeds during Germination. 1665 23

Dicoumarol, a competitive inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), increases intracellular superoxide and affects cell growth of tumor cells. This work was set to establish a mechanistic link between dicoumarol, superoxide and cell cycle alterations in HL-60 cells. Using ES936, a mechanism-based irreversible inhibitor of NQO1, we demonstrate that NQO1 inhibition is not a major factor involved in superoxide boost. Mitochondrial Complexes II, III and IV were directly inhibited by dicoumarol. Succinate, which inhibits superoxide generation by reversed electron flow in Complex II, significantly decreased superoxide boost in dicoumarol-treated cells and in isolated mitochondria incubated with dicoumarol and decylubiquinol. Superoxide generation in cells was strongly potentiated by blocking the quinone site of Complex II with thenoyltrifluoroacetone, supporting the involvement of cytochrome b560 to drive electrons for increasing superoxide. Simultaneous inhibition of the mitochondrial chain upstream ubiquinone and displacement of succinate from the Complex II active site is proposed as a major mechanism to explain how dicoumarol increases superoxide in HL-60 cells. Dicoumarol-treated cells accumulated in S phase due to the impairment of pyrimidine biosynthesis at dihydroorotate dehydrogenase step because blockade was overcome by addition of exogenous uridine or orotate, but not by dihydroorotate. We demonstrate for the first time that dicoumarol inhibits mitochondrial electron transport, induces superoxide release by reversed electron flow in Complex II, and inhibits pyrimidines biosynthesis. These actions must be taken into account when considering dicoumarol effects on cells.
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PMID:Dicoumarol impairs mitochondrial electron transport and pyrimidine biosynthesis in human myeloid leukemia HL-60 cells. 1712 68

Nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2), a transcription factor that regulates inducible expression of detoxifying enzymes, is critical in preventing N-nitrosobutyl(4-hydroxybutyl)amine (BBN)-induced urinary bladder carcinogenesis. To explore whether Nrf2 and the tumor suppressor p53 cooperatively act in tumor prevention, we investigated the susceptibility of Nrf2-/-::p53+/- mice to BBN-induced urinary bladder carcinogenesis. The incidence of BBN-induced urinary bladder carcinoma was 63.0% in Nrf2-/- mice (P = 0.115), 75.8% in p53+/- mice (P < 0.01) and 89.6% in Nrf2-/-::p53+/- mice (P < 0.01) compared with 37.9% in wild-type. Higher incidence of carcinoma was observed in Nrf2-/-::p53+/- mice when compared with either Nrf2-/- (P < 0.01) or p53+/- mice (P = 0.382). Similarly, muscular invasive carcinoma incidence was higher in Nrf2-/-::p53+/- mice (62.0%) than either wild-type (6.9%, P < 0.01), p53+/- (38.0%, P = 0.110) or Nrf2-/- mice (3.7%, P < 0.01). Furthermore, urinary concentrations of N-nitrosobutyl(3-carboxypropyl)amine, a proximate carcinogen of BBN, were only increased when Nrf2 but not p53 was disrupted. These results demonstrate that tumor susceptibility is synergistically exacerbated in Nrf2-/-::p53+/- mice due to poor detoxification and accelerated proliferation in comparison with either single mutant alone. BBN administration increased p53-mediated expression of p21, Mdm2 and Bax, and the inducible expression of p21 was significantly enhanced in Nrf2-/- mice. Conversely, modest increases in NAD(P)H dehydrogenase, quinone 1 (NQO1) and uridine diphosphate (UDP) glucuronosyltransferase 1A6 (UGT1A6) expression were observed in p53+/- compared with those of wild-type mice after BBN exposure. These results thus reveal potential interactions between p53 and Nrf2 and their gene batteries, and indicate that both factors cooperatively contribute to tumor prevention.
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PMID:Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis. 1760 69

Selenium deficiency has been reported to result in an extraordinary decrease of glutathione peroxidase (GSH-Px) and, reversely, an increase of detoxifying enzymes such as glutathione-S-transferase (GST), uridine-5'-diphosphate glucuronosyltransferase (UGT), nicotinamide-dependent quinine oxidoreductase (NQO1; DT-diaphorase), and epoxide hydrolase without significantly affecting cytochrome P450 activity. However, little is known about the effects on aldehyde oxidase 1 (AOX1) activity towards various kinds of aldehydes and N-heterocyclic aromatic compounds. The aim of this study is to clarify the effects of selenium deficiency on AOX1 in rats. As expected, selenium deficiency was confirmed by the extremely low activity of GSH-Px along with the increased activities of GST and DT-diaphorase. AOX1 activity towards vanillin and (S)-RS-8359 was increased by selenium deficiency, and that corresponded to an increase of AOX1 protein level but not to a decreased AOX1 mRNA level. It has been documented that the assembly of the catalytically active holoenzyme forms of the molybdo-flavoenzyme family is very complex and is controlled through transcriptional and translational events by many gene products. In addition, selenium deficiency has been known to cause oxidative stress that leads to an increase of AOX1 activity. Furthermore, aldehyde oxidase homolog 1 (AOH1) with properties similar to AOX1 is present in rodent liver. All the reports suggest that the mechanisms by which selenium deficiency increases AOX1 activity are highly complicated and investigated from different points of view.
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PMID:Effects of selenium deficiency on aldehyde oxidase 1 in rats. 1918 74

A substantial part of the interindividual variability in response to drugs and xenobiotics is related to genetically-determined impairment in drug metabolism. Several drug-metabolising enzymes are polymorphic in humans and often polymorphisms are strongly related to altered drug biodisposition and to the risk of developing adverse effects. Drugs used in general anaesthesia undergo polymorphic metabolism. Among these, halothane is metabolized by cytochrome P450 (CYP) 2E1 and, to a lesser extent, by CYP3A4 and CYP2A6. CYP2E1 also plays a key role in the metabolism of isoflurane, sevoflurane, enflurane and desflurane. CYP2B6, CYP3A4 and CYP2C9 play a relevant role in the metabolism of ketamine. The enzymes involved in the metabolism of thiopental and etomidate remains to be elucidated. Propofol is metabolized mainly by glucuronidation by uridine diphosphate-glucuronosyltransferases (UGTs) and by hydroxylation by CYP2B6 and CYP2C enzymes. The enzymes SULT1A1 and NQO1 participate in later steps in propofol metabolism. All the above-mentioned anaesthetic-metabolising enzymes are polymorphic in man. The present review analyzes the importance of enzymes in the metabolism of anaesthetics and common polymorphisms related to the biotransformation of general anaesthetics and it raises hypotheses on genetic and non-genetics factors related to altered response to anaesthetics that require further investigation. Based on functional relevance and allele frequencies, we identify the most promising targets for the clinical use of pharmacogenomic techniques in anaesthesia to prevent altered pharmacokinetics or adverse drug effects.
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PMID:Polymorphic drug metabolism in anaesthesia. 1944 86

Genetic polymorphisms in xenobiotic metabolizing enzymes can have profound influence on enzyme function, with implications for chemical clearance and internal dose. The effects of polymorphisms have been evaluated for certain therapeutic drugs but there has been relatively little investigation with environmental toxicants. Polymorphisms can also affect the function of host defense mechanisms and thus modify the pharmacodynamic response. This review and analysis explores the feasibility of using polymorphism data in human health risk assessment for four enzymes, two involved in conjugation (uridine diphosphoglucuronosyltransferases [UGTs], sulfotransferases [SULTs]), and two involved in detoxification (microsomal epoxide hydrolase [EPHX1], NADPH quinone oxidoreductase I [NQO1]). This set of evaluations complements our previous analyses with oxidative and conjugating enzymes. Of the numerous UGT and SULT enzymes, the greatest likelihood for polymorphism effect on conjugation function are for SULT1A1 (*2 polymorphism), UGT1A1 (*6, *7, *28 polymorphisms), UGT1A7 (*3 polymorphism), UGT2B15 (*2 polymorphism), and UGT2B17 (null polymorphism). The null polymorphism in NQO1 has the potential to impair host defense. These highlighted polymorphisms are of sufficient frequency to be prioritized for consideration in chemical risk assessments. In contrast, SNPs in EPHX1 are not sufficiently influential or defined for inclusion in risk models. The current analysis is an important first step in bringing the highlighted polymorphisms into a physiologically based pharmacokinetic (PBPK) modeling framework.
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PMID:Genetic polymorphism in metabolism and host defense enzymes: implications for human health risk assessment. 2066 11

Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost > 1 million deaths reported annually worldwide, remains a devastating disease with no known effective cure. Hence, chemopreventive strategies come into play, offering an effective and safe mode of treatment, ideal to ward off potential cancer risks and mortality. A major predisposing condition, pertinent to the development and progression of HCC is oxidative stress. We previously reported a striking chemopreventive effect of anthocyanin-rich black currant skin extract (BCSE) against diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats. The current study aims to elucidate the underlying antioxidant mechanisms of black currant anthocyanins implicated in the previously observed chemopreventive effects against experimental hepatocarcinogenesis. Dietary BCSE (100 and 500 mg/kg) administered four weeks before and 18 weeks after DENA challenge decreased abnormal lipid peroxidation, protein oxidation, and expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in a dose-responsive fashion. Mechanistic studies revealed that BCSE upregulated the gene expression of a number of hepatic antioxidant and carcinogen detoxifying enzymes, such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase isoenzymes, in DENA-initiated animals. Protein and mRNA expressions of nuclear factor E2-related factor 2 (Nrf2) were substantially elevated with BCSE treatment, providing a direct evidence of a coordinated activation of the Nrf2-regulated antioxidant pathway, which led to the upregulation of a variety of housekeeping genes. The results of our study provide substantial evidence that black currant bioactive anthocyanins exert chemopreventive actions against DENA-inflicted hepatocarcinogenesis by attenuating oxidative stress through activation of Nrf2 signaling pathway.
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PMID:Black currant anthocyanins abrogate oxidative stress through Nrf2- mediated antioxidant mechanisms in a rat model of hepatocellular carcinoma. 2287 20

A diet rich in fat is considered a primary risk factor for CVD, cancer and failures in metabolism and endocrine functions. Hyperlipidaemia generates oxidative stress and weakens antioxidant defences as well as metabolic detoxification systems. Brassicaceae are vegetables rich in glucosinolates and isothiocyanates, affecting enzymatic antioxidant as well as phase II enzymes and conceivably counteracting high-fat diet (HFD)-associated pathologies. The protective role of Tuscan black cabbage (a variety of kale) sprout extract (TBCSE) intake against HFD alterations was here studied. The effects on rat hepatic antioxidant as well as detoxifying enzymes, and serum lipid- and body weightlowering properties of TBCSE, were investigated. Feeding the animals with a HFD for 21 d increased body as well as liver weights, and induced hyperlipidaemia, as confirmed by a higher serum lipid profile v. control diet. Daily intragastric administration of TBCSE to HFD-fed rats lowered serum total cholesterol, TAG and NEFA. Body and liver weight gains were also reduced. Antioxidant (catalase, NAD(P)H:quinone reductase, oxidised glutathione reductase and superoxide dismutase) and phase II (glutathione S-transferase and uridine diphosphate glucuronosyl transferase) enzymes were down-regulated by the HFD, while the extract restored normal levels in most groups. Generation of toxic intermediates, and membrane fatty acid composition changes by the HFD, might account for the altered hepatic antioxidant and detoxifying enzyme functions. The recovering effects of TBCSE could be attributed to high flavonoid, phenolic and organosulphur compound content, which possess free-radical-scavenging properties, enhance the antioxidant status and stimulate lipid catabolism. TBCSE intake emerges to be an effective alimentary strategy to counteract the perturbations associated with a diet rich in fat.
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PMID:Protective effect of Tuscan black cabbage sprout extract against serum lipid increase and perturbations of liver antioxidant and detoxifying enzymes in rats fed a high-fat diet. 2343 61


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