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)

Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-di-N-oxide, SR 4233, WIN 59075) is a bioreductive antitumor agent with a high selective toxicity for hypoxic cells. The selective hypoxic toxicity of TPZ results from the rapid reoxidation of the one-electron reduction product, the TPZ radical, in the presence of molecular oxygen with the concomitant production of superoxide radical. Under hypoxia the TPZ radical kills cells by causing DNA double-strand breaks and chromosome aberrations. However, the mechanism of aerobic cytotoxicity is still a matter of debate. In this study, we investigated the mechanism of aerobic cytotoxicity by adapting human lung adenocarcinoma A549 cells to aerobic TPZ exposure and characterizing the changes associated with drug resistance. The adapted cells were resistant to aerobic TPZ exposures (with dose-modifying factors of up to 9.2), although hypoxic sensitivity was largely unchanged. Relative to the parental A549 cell line, adaptation to continuous aerobic TPZ exposure resulted in increased levels of manganese superoxide dismutase (up to 9.4-fold), moderate increases in glutathione reductase (up to 2.1-fold), and loss of both quinone oxidoreductase (DT-diaphorase) activity and NADPH cytochrome P450 reductase activity. There was essentially no change in the activity of the cytoplasmic form of superoxide dismutase (CuZnSOD), catalase, or glutathione peroxidase. The increased activity of antioxidant enzymes in the resistant cell lines (in particular MnSOD) strongly suggests that reactive oxygen species are, in large part, responsible for the toxicity of TPZ under aerobic conditions, and is consistent with aerobic and hypoxic drug cytotoxicity resulting from different mechanisms.
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PMID:Adaptation of human tumor cells to tirapazamine under aerobic conditions: implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity. 927 29

In our studies to find natural compounds with chemopreventive efficacy in foods, using azoxymethane (AOM)-induced colonic aberrant crypt foci and colonic mucosal cell proliferation as biomarkers, a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate (ACA), present in the edible plant Languas galanga from Thailand was found to be effective. This study was conducted to test the ability of ACA to inhibit AOM-induced colon tumorigenesis when it was fed to rats during the initiation or post-initiation phase. Male F344 rats were given three weekly s.c. injections of AOM (15 mg/kg body weight) to induce colonic neoplasms. They were fed diet containing 100 or 500 ppm ACA for 4 weeks, starting one week before the first dosing of AOM (the initiation feeding). The other groups were fed the ACA diet for 34 weeks, starting one week after the last AOM injection (the post-initiation feeding). At the termination of the study (week 38), AOM had induced 71% incidence of colonic adenocarcinoma (12/17 rats). The initiation feeding with ACA caused significant reduction in the incidence of colon carcinoma (54% inhibition by 100 ppm ACA feeding and 77% inhibition by 500 ppm ACA feeding, P = 0.03 and P = 0.001, respectively). The post-initiation feeding with ACA also suppressed the incidence of colonic carcinoma (45% inhibition by 100 ppm ACA feeding and 93% inhibition by 500 ppm ACA feeding, P = 0.06 and P = 0.00003, respectively). Such inhibition was dose-dependent and was associated with suppression of proliferation biomarkers, such as ornithine decarboxylase activity in the colonic mucosa, and blood and colonic mucosal polyamine contents. ACA also elevated the activities of phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. These results indicate that ACA could inhibit the development of AOM-induced colon tumorigenesis through its suppression of cell proliferation in the colonic mucosa and its induction of GST and QR. The results confirm our previous finding that ACA feeding effectively suppressed the development of colonic aberrant crypt foci. These findings suggest possible chemopreventive ability of ACA against colon tumorigenesis.
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PMID:Chemoprevention of azoxymethane-induced rat colon carcinogenesis by a xanthine oxidase inhibitor, 1'-acetoxychavicol acetate. 936 29

In our previous short-term experiment, Citrus auraptene inhibited the development of azoxymethane (AOM)-induced aberrant crypt foci, which are precursor lesions for colorectal carcinoma. In the present study, the possible inhibitory effect of dietary administration of auraptene was investigated using an animal colon carcinogenesis model with a colon carcinogen AOM. Male F344 rats were given s.c. injections of AOM (15 mg/kg body weight) once a week for 3 weeks to induce colon neoplasms. They also received diets containing 100 or 500 ppm auraptene for 4 weeks in groups of "initiation" feeding, starting 1 week before the first dosing of AOM. The diets containing auraptene were also given to rats for 38 weeks in groups of "postinitiation" feeding. At the termination of the study (38 weeks), dietary administration of auraptene caused dose-dependent inhibition in AOM-induced large bowel carcinogenesis. Auraptene feeding during the initiation phase reduced the incidence of colon adenocarcinoma by 49% at 100 ppm (P = 0.099) and 65% at 500 ppm (P = 0.0075). Auraptene administration during the postinitiation phase inhibited the incidence of colon adenocarcinoma by 58% at 100 ppm (P = 0.021) and 65% at 500 ppm (P = 0.0075). Also, the multiplicity of colon carcinoma was significantly reduced by initiation feeding at a dose level of 500 ppm (P < 0.01) and postinitiation feeding at a level of 100 and 500 ppm (P < 0.05 and P < 0.01, respectively). Feeding of auraptene suppressed the expression of cell proliferation biomarkers (ornithine decarboxylase activity and polyamine content) in the colonic mucosa and reduced the production of aldehydic lipid peroxidation [malondialdehyde and 4-hydroxy-2(E)-nonenal]. In addition, auraptene increased the activities of Phase II drug-metabolizing enzymes (glutathione S-transferase and quinone reductase) in the liver and colon. These findings suggest that the inhibitory effects of auraptene on AOM-induced colon tumorigenesis at the initiation level might be associated, in part, with increased activity of Phase II enzymes, and those at the postinitiation stage might be related to suppression of cell proliferation and lipid peroxidation in the colonic mucosa.
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PMID:Citrus auraptene exerts dose-dependent chemopreventive activity in rat large bowel tumorigenesis: the inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of phase II drug-metabolizing enzymes. 963 77

Mice develop lung tumors similar in their histogenesis and molecular features to peripheral adenocarcinomas in humans. The advantage of this model system is that events early in tumorigenesis can be delineated and their biological consequences tested by transgenic and knockout strategies. Both human and murine adenocarcinomas contain Kras mutations; in mice these occur within weeks following carcinogen administration. Decreased expression of similar tumor suppressor genes occur in both species due to mutation, deletion, altered DNA methylation, or unknown mechanisms. These genes include p15, p16, Rb, cyclin D1, p53, Apc, Mcc, and Gjal. Some genes have only been examined in one of these species, such as the deletions in chromosome 3p and the overexpression of bcl 2 in human adenocarcinoma. Not all molecular changes are identical to the two species, however. Quinone oxidoreductase (DT-diaphorase) levels rise in the human tumors but fall in the mouse; the extent of both changes is very dramatic. Similarly, EGF-receptor content often increases in human lung adenocarcinomas but decreases in the mouse tumors. In general, however, the nature of the molecular changes is quite similar.
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PMID:Molecular comparison of human and mouse pulmonary adenocarcinomas. 965 82

Intracellular metabolism of chromium(VI) [Cr(VI)] may lead to oxidative stress and this may account for the ability of Cr(VI) to act as a complete carcinogen. Therefore, we examined the effects of Cr(VI) treatment on the expression of oxidative stress genes in normal human lung LL 24 cells and human lung adenocarcinoma A549 cells. RT-PCR and northern blot analyses were used to determine the steady-state mRNA levels of catalase, glutathione S-transferase, glutathione reductase, Cu/Zn- and Mn-superoxide dismutases, glutathione peroxidase, NAD(P)H:quinone oxidoreductase, heme oxygenase and interleukin 8 in control cells and cells treated with 5-200 microM of Cr(VI). We found that only expression of the heme oxygenase gene is strongly elevated under the treatment with Cr(VI), and only in normal human lung LL 24 cells. Our data showed that even in the absence of Cr(VI) treatment, the level of heme oxygenase gene expression is much higher in A549 cells than in LL 24 cells. As glutathione is believed to play a protective role in cells against different forms of oxidative stress, we studied the correlation between intracellular glutathione levels and the inducibility of the heme oxygenase gene after treatment of cells with Cr(VI). Our results demonstrate that glutathione levels are increased by 35 % of control values in LL 24 cells treated with Cr(VI). The data obtained indicate that heme oxygenase, known to be a stress-inducible gene, may be involved in cellular pathways critical to the carcinogenic activity of Cr(VI) in normal human lung cells. Intracellular glutathione levels and reactive oxygen species do not appear to be primarily responsible for the stress response, induced by Cr(VI) in the studied human cells.
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PMID:Effects of Cr(VI) on the expression of the oxidative stress genes in human lung cells. 974 36

NAD(P)H:quinone oxidoreductase (NQO1) is a flavoenzyme that catalyzes the two-electron reduction of quinones and related compounds. With the use of biochemical assays, NQO1 has been shown to be overexpressed in many types of cancer, including non-small cell lung cancer (NSCLC). NQO1 can bioactivate antitumor quinones such as mitomycin C, and new quinone-based drugs are currently being developed to target this enzyme in tumors such as NSCLC. Because there is no information on the cell-specific expression of NQO1 in lung, the purpose of this study was to examine the expression of NQO1 in human NSCLC, small cell lung cancer, carcinoid lung tumors, and normal lung using immunohistochemistry. A high level of NQO1 protein expression was detected by immunohistochemistry in NSCLC (adenocarcinoma, squamous cell carcinoma, and bronchoalveolar carcinoma), but no NQO1 protein could be detected in small cell lung cancer or carcinoid lung tumors. In addition, NQO1 protein expression was examined by immunohistochemistry in normal lung tissue. A high level of NQO1 protein expression was detected by immunohistochemistry in normal lung respiratory epithelium, with the highest levels of expression observed in ciliated columnar epithelial cells. Significant amounts of NQO1 protein were also detected in the vascular endothelium and adipocytes. These data demonstrate that NQO1 is overexpressed in NSCLC. Cells in normal lung also contain marked NQO1 protein and may be damaged by drugs activated by NQO1. These data validate NSCLC as a target for NQO1-directed agents and suggest that the potential for lung toxicity be considered in the preclinical development of quinone-based antitumor drugs.
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PMID:Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors. 974 20

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] is a synthetic dithiolethione with chemopreventive activity against carcinogen-induced neoplasia of liver, lung, and colon in several animal model systems. Protection from tumor formation is associated with elevation of Phase II enzymes, including glutathione (GSH) transferase and NAD(P)H:quinone oxidoreductase (DT-diaphorase) in experimental carcinogenesis models in vivo. To investigate the time and dose relationships of the pharmacological action of oltipraz and to develop a model for its investigation, a human colon adenocarcinoma HT29 cell line was primarily used. In this cell line, oltipraz resulted in increased activity of both GSH transferase and DT-diaphorase. At the maximum effective concentration (100 microM), the elevation of GSH transferase was 3-fold and that of DT-diaphorase was 2-fold. The optimal duration of oltipraz exposure to HT29 cells was 24 h, following which the peak in enzyme activity was observed at 24 h after removal of the drug, and activity had almost returned to control levels after 72 h in drug-free media. Steady-state mRNA levels for DT-diaphorase were observed to increase during the period of drug exposure and remained elevated, even as catalytic activities declined to control levels, suggesting additional mechanisms for control of the activity of this enzyme. More prolonged drug exposure was associated with less induction of the detoxication enzymes, prompting an investigation of the possible toxicity of oltipraz to these cells. Although the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed inhibition of proliferation (IC50, 100 microM oltipraz), a clonogenic assay demonstrated no loss of clonogenicity. Oltipraz is known to be extensively metabolized in many species; two major metabolites include a 3-ketone (metabolite 2, M2) and a molecular rearrangement to a pyrrolopyrazine derivative (metabolite 3, M3), numerous conjugates of which are formed in vivo. To investigate the potential cause of the lag in response, we synthesized two major oltipraz metabolites (M2 and M3) and tested their efficacy in enzyme induction. The activity of DT-diaphorase was induced similarly by both oltipraz and M2 (2.6- versus 2.8-fold baseline) at 100 microM, whereas M3 was inactive at all concentrations. M2 also resulted in a 5.8-fold elevation of steady-state DT-diaphorase mRNA levels. Both enzyme activity and steady-state mRNA peaked at 24 h as with the parent compound. Thus, the oxidative desulfuration of oltipraz results in the formation of an active metabolite, but this process is not rate limiting for the induction of detoxicating enzymes. These data support the use of intermittent schedules in oltipraz in clinical trials of chemoprevention because of evidence of attenuation of response. The metabolite M2, but not M3, is as active as the parent compound and may be considered for clinical development in its own right.
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PMID:Cellular kinetics of induction by oltipraz and its keto derivative of detoxication enzymes in human colon adenocarcinoma cells. 981 50

Allelic variations at the NQO1 locus encoding for NAD(P)H:quinone oxidoreductase have recently been implicated in carcinogenesis, cancer chemoprevention and chemotherapy. Two naturally occurring alleles differ at nucleotide position 609 with the variant allele leading to diminished or absent enzyme activity. Using polymerase chain reaction-restriction fragment length polymorphic analysis, NQO1 genotyping was performed in DNA from blood cells from 54 patients with prostatic adenocarcinoma, 49 patients with benign prostatic hyperplasia and 100 healthy control subjects. Prostatic adenocarcinoma patients and healthy controls demonstrated almost identical genotype distribution and frequencies of the variant allele (17.6 versus 17.5%). The variant allele was slightly more frequent in benign prostatic hyperplasia patients (23.5%). Established prostate cancer-derived cell lines LnCAP, DU-145, and PC-3 demonstrated NQO1 wild-type genotype. Our study does not support the hypothesis that the variant NQO1 allele is a risk modifier for prostatic adenocarcinoma and/or benign prostatic hyperplasia in the Caucasian population.
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PMID:609 C --> T polymorphism in NAD(P)H:quinone oxidoreductase gene in patients with prostatic adenocarcinoma or benign prostatic hyperplasia. 1007 23

The modifying effect of dietary exposure to a flavonoid morin during the initiation and post-initiation phases of azoxymethane (AOM)-initiated colorectal carcinogenesis was investigated in male F344 rats. A total of 55 animals were initiated with AOM by weekly s. c. injections of 15 mg/kg body wt for 3 weeks to induce colorectal neoplasms. Rats were fed a diet containing 500 p.p.m. morin for 5 ('initiation feeding') or 28 ('post-initiation feeding') weeks. Other groups contained rats treated with morin alone (500 p.p.m. in diet) and untreated rats. At the end of the study (32 weeks), the incidence of adenocarcinoma in the large intestine of rats initiated with AOM together with (43%) or followed by (29%) a diet containing morin was smaller than that of rats given AOM alone (75%). A significant difference was found between 'post-initiation feeding' and untreated groups (P = 0.023). Although both 'initiation feeding' and 'post-initiation feeding' of morin reduced polyamine levels in colorectal mucosa and blood, 'post-initiation feeding' of morin significantly decreased the proliferating cell nuclear antigen-positive index in aberrant crypt foci. 'Post-initiation feeding' of morin significantly elevated glutathione S-transferase and quinone reductase activities in the liver and large bowel, but 'initiation feeding' caused a significant elevation of these enzymes activities only in the large bowel. These results indicate that morin could exert a weak chemopreventive effect on large bowel tumorigenesis induced by AOM when fed during the post-initiation phase.
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PMID:Modifying effects of a flavonoid morin on azoxymethane-induced large bowel tumorigenesis in rats. 1042 95

Lung cancer is one of the leading causes of death in Taiwan since 1996. Genetic variation in metabolic activation or detoxification enzymes has been associated with the occurrence of lung cancer. NAD(P)H:quinone oxidoreductase (NQO1) enzyme is a cytosolic two-electron reductase thought to be involved in bioactivation and detoxification of environmental carcinogens. The possible association between NQO1 genetic polymorphism and lung cancer risk was examined among 95 male smokers without cancer and 100 male smokers with lung cancer in Taiwan. There was no significant difference in the proportion of wild-type NQO1 among all cancer cases and controls. When cases were stratified according to histological subtypes, the wild-type NQO1 was more common in adenocarcinoma than in controls. The odds ratio was 2.93 (95% confidence interval, 1.23-7.02; p = .02). This is the first observation for the positive association of this locus with lung cancer in an Asian population. These results suggest that NQO1 polymorphism is an important genetic risk factor for lung adenocarcinoma among smokers in Taiwan.
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PMID:NAD(P)H: quinone oxidoreductase polymorphism and lung cancer in Taiwan. 1059 87


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