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:1.6.99.3 (diaphorase)
5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Highly purified cytochrome P-450 reductase (also called cytochrome c reductase; EC 1.6.2.4.) and NADPH were used to generate superoxide radical (O2.-) from 11 different heterocyclic amines (HCAs) as identified by electron spin resonance spectroscopy using the spin trapping method with 5,5-dimethyl-1-pyrroline N-oxide (DMPO). The signal intensity of DMPO-OOH(-O2-) (i.e., the DMPO spin adduct of O2.-) was strongest for 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ). The O2.- generation with HCAs decreased in the following order: 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx) = 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) > 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (diMeIQx) > or = other HCAs; O2.- generation was lowest with 2-amino-3-methyl-9H-pyrido[2,3-b]indole .CH3COOH (MeA alpha C). By using Lineweaver-Burk plots, Km values of cytochrome P-450 reductase for mitomycin C, IQ, and MeIQ were determined to be 1.60 x 10(-6) M, 1.97 x 10(-5) M, and 2.83 x 10(-6) M, respectively. The present findings have important implications for carcinogenesis because of the known effect of oxygen radicals on cell proliferation.
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PMID:Evidence of direct generation of oxygen free radicals from heterocyclic amines by NADPH/cytochrome P-450 reductase in vitro. 133 93

Topical application on rat oral mucosa of the chemical 4-nitroquinoline 1-oxide (4NQO) has been shown to produce squamous cell carcinomas on the posterior tongue and/or the posterior hard palate. 4NQO is broken down in vivo by a diaphorase, 4NQO reductase (E.C.1.6.99.2), to produce an active molecule believed to be responsible for carcinogenesis. It has been shown that there are higher concentrations of 4NQO reductase in oesophageal mucosa compared with elsewhere in the gastrointestinal tract. The purpose of these experiments was to compare the distribution of certain diaphorases in the oral mucosa. Samples of rat tongue and cheek epithelia were homogenized, then ultracentrifuged to provide mixed cytosol and microsome fractions from the epithelial cells. A spectrophotometer was used to measure the variation in absorbance at 340 nm of NADH consumed by reduction of 4NQO by enzymes present in the tissue extracts. A histochemical technique was used to compare the activity of NADH diaphorase, NADP diaphorase and glucose-6-phosphate dehydrogenase at different sites of the oral mucosa. Statistical analysis showed that there were significant (P less than 0.01) differences between the activities of all three enzymes at different sites of the oral mucosa. In each case, a higher activity was found at the sites of high incidence of squamous cell carcinoma. A lower activity was found at sites where carcinomas did not occur.
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PMID:A relationship found between intra-oral sites of 4NQO reductase activity and chemical carcinogenesis. 211 96

The metabolic activation or detoxification of mutagens and carcinogens of several chemical classes was investigated in the presence of various rat liver and lung subcellular fractions and of dicoumarol, a specific inhibitor of DT diaphorase activity. His- Salmonella typhimurium strains were used as targets of mutagenicity. Dicoumarol partially prevented the metabolic activation of some promutagens, such as the heterocyclic amines 2-amino-3,4-dimethylimidazo[4,5-f]quinoline and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, and a cigarette smoke condensate. Moreover, detailed experiments, also using purified enzyme, confirmed the participation of DT diaphorase in the metabolic reduction of 4-nitroquinoline N-oxide 4NQO and of hexavalent chromium [Cr(VI)] compounds. The results obtained provide evidence for broad involvement of DT diaphorase in the metabolism of both organic and inorganic mutagens and carcinogens. Moreover, they suggest a dual role of this enzyme, providing not only a cellular detoxifying system but also, with a few substrates, an activating mechanism.
Carcinogenesis 1988 Apr
PMID:Influence of DT diaphorase on the mutagenicity of organic and inorganic compounds. 245 76

At variance with Cr(III), Cr(VI) compounds easily cross cell membranes and exert genotoxic effects. No metabolic oxidation of Cr(III) could be detected, whereas Cr(VI) reduction was observed in the presence of body fluids and subcellular fractions of various tissues from several animal species. The differential efficiency of this process may account for the selection of target tissues in Cr(VI) carcinogenesis. For instance, reduction by saliva and gastric juice may explain a lack of carcinogenicity by the oral route; reduction inside erythrocytes may explain a lack of carcinogenicity at a distance from administration sites; reduction by the epithelial-lining fluid of terminal airways and by alveolar macrophages may be consistent with the occurrence of thresholds in lung carcinogenesis. Liver preparations displayed the top efficiency in reducing Cr(VI), whereas skeletal muscle, i.e., a typical target in experimental Cr(VI) carcinogenesis, had no detectable activity. Bronchial tree and peripheral lung parenchyma preparations from almost 100 individuals reduced Cr(VI) to a variable extent. The efficiency of lung parenchyma and of isolated alveolar macrophages was enhanced in cigarette smokers. In rats, Cr(VI) reduction by lung preparations was significantly stimulated by the repeated i.t. instillation of Cr(VI) itself. Among the electron donors (chiefly GSH) and enzymatic mechanisms responsible for the intracellular Cr(VI) reduction, such as cytochrome P-450 reductase, glutathione reductase, and aldehyde oxidase, an important role can be ascribed to cytosolic DT diaphorase activity, usually catalyzing a 2-electron reduction.
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PMID:Metabolic reduction of chromium, as related to its carcinogenic properties. 248 84

Carcinomas of the ethmoidal region of the nose are observed relatively frequently in cattle in several countries in tropical and subtropical latitudes. Viruses have been implicated as causative agents, but it has been observed that affected animals sometimes suffer from aflatoxicosis, and a role of aflatoxin B1 (AFB1) in the aetiology has also been proposed. We have examined whether the bovine nasal olfactory mucosa has a capacity to metabolize AFB1. The contents of cytochrome P-450 and cytochrome b5, and the NADPH cytochrome c reductase activity in the nasal olfactory mucosa have also been determined. Comparative experiments have been performed with the liver. Incubations with 3H-labelled AFB1 showed that the nasal olfactory mucosa has a much higher capacity than the liver to form lipid-soluble, water-soluble and tissue-bound AFB1-metabolites. High-resolution microautoradiography showed a strong localization of tissue-bound metabolites in the sustentacular cells in the apical portion of the olfactory surface epithelium and in Bowman's glands in the olfactory lamina propria mucosae. Especially in the sustentacular cells the labelling was preferentially located in the nuclei of the cells. Liquid chromatography of chloroform extracts of the nasal olfactory mucosa and the liver incubated with 3H-AFB1 showed formation of several metabolites. The dominating peak in both tissues was aflatoxin M1 (AFM1). However, the amount of AFM1 was higher in the nasal olfactory mucosa than in the liver, and the amounts and proportions of several other metabolites also differed markedly between the two tissues. The level of cytochrome P-450 in the nasal olfactory mucosa was found to be about one quarter of that in the liver, but the NADPH cytochrome c reductase activity was much higher in the nasal olfactory mucosa than in the liver. In addition, the cytochrome b5: cytochrome P-450 ratio was higher in the nasal olfactory mucosa than in the liver. The higher metabolism of AFB1 in the nasal olfactory mucosa than in the liver may be related to differences in the cytochrome P-450 isoenzyme profile. In addition, the microsomal electron transport to cytochrome P-450 may be facilitated by the high reductase: cytochrome P-450 ratio and the high cytochrome b5: cytochrome P-450 ratio in the nasal olfactory mucosa.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1989 Jun
PMID:Metabolism of aflatoxin B1 in the bovine olfactory mucosa. 249

The metabolism of chemical carcinogens was investigated in liver preparations from 28 captive woodchucks (Marmota monax). Of these, 23 were naturally infected with the woodchuck hepatitis virus (WHV), and eight also had primary hepatocellular carcinoma (PHC). Twenty-nine parameters were investigated in liver subcellular fractions, including cross-reactivity with HBsAg, and biochemical parameters, such as gamma-glutamyl transpeptidase, cytochrome P-450 and microsomal monooxygenases (aryl hydrocarbon hydroxylase, ethoxycoumarin and ethoxyresorufin deethylases, aminopyrine and dimethylnitrosamine demethylases, and testosterone 7 alpha-, 16 alpha- and 6 beta-hydroxylases), uridine 5'-diphosphoglucuronosyl transferase, GSH and related enzymes (peroxidase, reductase and S-transferase), as well as other cytosolic enzyme activities (glucose 6-phosphate and 6-phosphogluconate dehydrogenases, NADPH- and NADH-dependent diaphorases, and DT diaphorase). In addition, liver preparations were used in order to quantify the metabolic activation into bacterial mutagens of five procarcinogens (aflatoxin B1, the pyrolysis products Trp-P-2 and MeIQ, 2-aminofluorene and dimethylnitrosamine) and the decrease of potency of three direct-acting mutagens (sodium dichromate, ICR 191 and 4-nitroquinoline 1-oxide). WHV infection produced a significant stimulation of carcinogen metabolism, as shown by the simultaneous change in detoxification parameters (GSH depletion) and activation indices (enhancement of microsomal monooxygenases and of procarcinogen activation into mutagenic metabolites). There were no significant differences between WHV-positive samples from animals without PHC and the noncancerous tissue of PHC-bearing animals, whereas a decrease of both activation and detoxification indices was recorded in the tumorous tissue. There was a considerable interindividual variability among WHV carriers, which was tentatively ascribed to genetic factors. Pregnancy was the only known factor influencing the results in WHV carriers. However, even by excluding pregnant animals, the effects on carcinogen metabolism produced by WHV infection were still statistically significant. These results, together with previous data obtained in humans, revealed that metabolic factors may play a role in the synergism between viral hepatitis and chemical hepatocarcinogens in the etiopathogenesis of PHC.
Carcinogenesis 1989 Jun
PMID:Enhanced metabolic activation of chemical hepatocarcinogens in woodchucks infected with hepatitis B virus. 272 Sep 3

Three isomeric quinone metabolites of the environmental carcinogen benzo[a]pyrene undergo reversible, univalent oxidation-reduction cycles involving the corresponding benzo[a]pyrene diols and intermediate semiquinone radicals. Under anaerobic conditions, benzo[a]pyrene 1,6-dione, benzo[a]pyrene 3,6-dione, and benzo[a]pyrene 6,12-dione are readily reduced by mild biological agents such as NADH and glutathione. The benzo[a]pyrene diols, in turn, are very rapidly autooxidized to diones when exposed to air. Substantial amounts of hydrogen peroxide are produced during these autooxidations. The benzo[a]pyrene diol/benzo[a]pyrene dione interconversions proceed by one-electron steps; the corresponding semiquinone radicals were detected as intermediates when the reactions were carried out at high pH. Benzo[a]pyrene diones are electron-acceptor substrates for NADH dehydrogenase. Catalytic amounts of these metabolites, together with this respiratory enzyme, function as cyclic oxidation-reduction couples to link NADH and molecular oxygen in the continuous production of hydrogen peroxide. Benzo[a]pyrene diones induce strand scissions when incubated with T7 DNA. The damage is modified by conditions that indicate that reduced oxygen species propagate the reactions responsible for strand scission. Benzo[a]pyrene diones are cytotoxic at low concentrations to cultured hamster cells. The cytotoxic effect can be substantially reduced by depletion of oxygen from the growth medium and the atmosphere in which the cells are incubated. The results support the hypothesis that the biological activity of benzo[a]pyrene diones is due to the regenerative oxidation-reduction cycles involving quinone and hydroquinone forms; activated oxygen species and semiquinone radicals formed during these cycles are most likely responsible for the observed cytotoxic action. The role of activated oxygen species in carcinogenesis is discussed.
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PMID:Benzo[a]pyrene dione-benzo[a]pyrene diol oxidation-reduction couples; involvement in DNA damage, cellular toxicity, and carcinogenesis. 300 1

The purpose of the present investigation was to determine the effects of dietary selenium deficiency or excess on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary neoplasia in rats and to delineate whether selenium-mediated modification of mammary carcinogenesis was associated with changes in carcinogen:DNA adduct formation and activities of liver microsomal enzymes that are involved in xenobiotic metabolism. Female Sprague-Dawley rats were divided into three groups from weaning and were maintained on one of three synthetic diets designated as follows: selenium deficient (less than 0.02 ppm); selenium adequate (0.2 ppm); or selenium excess (2.5 ppm). For the DMBA binding and DNA adduct studies, rats were given a dose of [3H]DMBA p.o. after 1 month on their respective diets. Results from the liver and the mammary gland indicated that neither selenium deficiency nor excess had any significant effect on the binding levels, which were calculated on the basis of total radioactivity isolated with the purified DNA. Furthermore, it was found that dietary selenium intake did not seem to affect quantitatively or qualitatively the formation of DMBA:DNA adducts in the liver. Similarly, in a parallel group of rats that did not receive DMBA, the activities of aniline hydroxylase, aminopyrine N-demethylase, and cytochrome c reductase were not significantly altered by dietary selenium levels. Concurrent with the above experiments, the effect of dietary selenium intake on carcinogenesis was also monitored. Results of this experiment indicated that selenium deficiency enhanced mammary carcinogenesis only when this nutritional condition was maintained in the postinitiation phase. Likewise, an excess of selenium intake inhibited neoplastic development only when this regimen was continued after DMBA administration. In either case, deficient or excess selenium at the time of carcinogenic insult failed to produce a significant effect on subsequent tumor yield, if selenium intake was returned to normal during the proliferative phase of tumor growth. Based on the results of these studies, it is suggested that selenium-mediated modification of mammary tumorigenesis is not exerted via alterations in carcinogenic initiation (i.e., metabolism or DNA adduct formation).
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PMID:Effects of selenium on 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis and DNA adduct formation. 391 75

Chloracne is a follicular hyperkeratosis produced by exposure to certain halogenated aromatic compounds. The rabbit ear bioassay has been used successfully for testing the acnegenic activity of compounds, but the lack of reference data in this species limits its usefulness in correlating chloracne to other toxic effects such as skin carcinogenesis. In this study, a prototype chloracnegen, 3,4,3',4'-tetrachloroazoxybenzene (TCAOB), was used. Five strains of mice (hairless, rhino, rhino+, DBA/2J, and C57BL/6) were treated topically with 100 microliters of 0.001, 0.01, or 0.1% TCAOB daily for 3-9 wk. Skin and liver histology were performed and hepatic enzyme activities measured. At the 0.001% TCAOB level, induction of hepatic aniline hydroxylase and cytochrome P-450 occurred in the C57BL/6 mice and induction of cytochrome c reductase occurred in the rhino mice. Dose-dependent gross and histologic skin lesions, characteristic of follicular hyperkeratosis, were observed in the rhino and hairless strains at the 0.01% and 0.1% levels. These two strains also had induction of hepatic cytochrome c reductase, cytochrome P-450, and aniline hydroxylase at TCAOB concentrations of 0.01 or 0.1%. These results suggest that the rhino and hairless strains of mice may be useful in the study of chloracne.
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PMID:Assessment of the chloracnegenic response induced by 3,4,3',4'-tetrachloroazoxybenzene in mice. 400 34

To improve identification of preneoplastic bladder cancer cells, we have studied two enzyme histochemical changes in bladder tumors induced in male Fisher 344 rats by the carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine. In early areas of focal nodular hyperplasia there was a dramatic increase in staining for NADH:menadione oxidoreductase (diaphorase)activity. In nonfocal areas as well, there were many individual cells with intense staining, while the controls were of uniform moderate staining. Large papillomas and carcinomas often showed heterogeneous staining. gamma-Glutamyltranspeptidase (GGT) was absent from normal urothelium and from all tumors except the most advanced carcinomas and large papillomas. In old, carcinogen-exposed animals, GGT activity was seen in the luminal surface of tumors and in the interlesion urothelium. In newborn rats and in rats with regenerative hyperplasia following wounding of the urothelium, the diaphorase staining was less than that in the untreated adult. Our findings suggest that increased diaphorase activity may serve to identify early islands of carcinogen-induced, enzymatically altered bladder cells, while GGT will not.
Carcinogenesis 1982
PMID:Histochemistry of NADH diaphorase and gamma-glutamyltranspeptidase in rat bladder tumors. 612 24


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