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

---

Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, has been shown to inhibit chemical carcinogenesis, possibly due to its ability to block the activation or to enhance the detoxification of chemical carcinogens. The present study was conducted to elucidate the biochemical mechanisms involved by characterizing the effects of PEITC on phase I and phase II xenobiotic-metabolizing enzymes. A single dose of PEITC to F344 rats (1 mmol/kg) decreased the liver N-nitrosodimethylamine demethylase (NDMAd) activity (mainly due to P450 2E1) by 80% at 2 h and the activity of NDMAd remained decreased by 40% at 48 h after treatment. The liver pentoxyresorufin O-dealkylase (PROD) activity and P450 2B1 protein level were elevated 10- and 7-fold at 24 h after treatment respectively. The liver microsomal ethoxyresorufin O-dealkylase (EROD) (mainly due to P450 1A) and erythromycin N-demethylase (mainly due to P450 3A) activities were decreased at 2-12 h after treatment and recovered afterwards. The lung microsomal PROD and EROD activities were not significantly affected; whereas, the nasal microsomal PROD and EROD activities were decreased by 40-50%. After a treatment with PEITC, the rates of oxidative metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were decreased in liver microsomes by 40-60% at 2 h and recovered gradually; the rates in lung microsomes were markedly decreased by 60-70% at 2 h and remained at the decreased level at 24 h; and the rates in nasal mucosa microsomes were decreased gradually with the lowest activities observed at 18 h (50%) followed by a gradual recovery. Furthermore, the treatment with PEITC resulted in a maximal 5-fold increase of NAD(P)H:quinone oxidoreductase and 1.5-fold increase of glutathione S-transferase activities in the liver, but the activities of these two enzymes were not significantly affected in the lung and nasal mucosa. The sulfotransferase activity in the liver was decreased by 32-48% at 24-48 h after treatment; the nasal activity was increased by 1.8- to 2.5-fold, but the lung activity was not significantly changed. The hepatic UDP glucuronosyltransferase activity was slightly decreased at 2 h but slightly increased at 48 h after treatment, but no changes were observed for the lung and nasal activities. The study demonstrates that PEITC selectively affects xenobiotic-metabolizing enzymes in the liver, lung and nasal mucosa and it is especially effective in inhibiting the P450-dependent oxidation of NNK in the lung and of NDMA in the liver.
...
PMID:Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats. 147 25

Dimethyl fumarate and dimethyl maleate are potent inducers of cytosolic NAD(P)H:(quinone acceptor) oxidoreductase (here designated quinone reductase) activity in Hepa 1c1c7 murine hepatoma cells in culture, whereas fumaric and maleic acids are much less potent, in agreement with the much greater reactivity of the esters as Michael reaction acceptors (P. Talalay, M. J. De Long, and H. J. Prochaska, Proc. Natl. Acad. Sci. USA, 85:8261-8265, 1988). Dimethyl fumarate also induced quinone reductase in mutants of the Hepa 1c1c7 cell line that were either defective in the Ah receptor or in cytochrome P1-450 activity, thereby establishing that this compound is a monofunctional inducer (H. J. Prochaska and P. Talalay, Cancer Res., 48: 4776-4782, 1988). Addition of dimethyl fumarate to the diet of female CD-1 mice and female Sprague-Dawley rats at 0.2-0.5% concentrations elevated cytosolic glutathione transferases and quinone reductase activities in a variety of organs, whereas much higher concentrations of fumaric acid were only marginally active. The widespread induction of such detoxication enzymes by dimethyl fumarate suggests the potential value of this compound as a protective agent against chemical carcinogenesis and other forms of electrophile toxicity. This proposal is supported by the finding that the concentrations of dimethyl fumarate required to obtain substantial enzyme inductions were well tolerated by rodents. Furthermore, the parent fumaric acid has low chronic toxicity and is a naturally occurring metabolic intermediate that is already in the food chain as an additive, and fumarate salts and esters are used for therapeutic purposes in man.
...
PMID:Induction of glutathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. 212 43

1. Strain variations among mice in terms of cytosolic DT-diaphorase activity were studied in liver, kidney, stomach and heart tissues with or without the administration of 3-tert-butyl-4-hydroxyanisole (BHA). 2. BHA induced DT-diaphorase activity in all strains examined, and the magnitude of induction varied depending on the strain and tissue. Among the 10 inbred strains tested, BALB/c and C57BL mice showed relatively large magnitudes of induction for liver DT-diaphorase, whereas C3H and CBA mice showed relatively small magnitudes. 3. Results of examinations of BALB/c-C3H-F1, -F2 and C57BL-CBA-F1 mice revealed that smaller magnitudes of induction of liver DT-diaphorase were inherited essentially as a dominant trait. The hereditary trait could be adequately explained by postulating two gene loci that regulate the magnitude of induction. 4. The possible significance of DT-diaphorase activity in chemical carcinogenesis was discussed.
...
PMID:Mouse strain variations in the magnitude of induction of liver DT-diaphorase and hereditary transmission of the trait. 250 67

Dehydroepiandrosterone (DHEA) is a naturally occurring C19-steroid that is found in the peripheral circulation of mammals, including humans. The feeding of DHEA to rodents has been shown to inhibit chemical carcinogenesis in colon, liver, and lung. Therefore, the effect of DHEA on hepatic enzyme activities that are associated with carcinogen metabolism was assessed. Microsomal NADPH-cytochrome P-450 reductase activity and the content of cytochrome b5 were induced 1.8- and 1.4-fold, respectively, upon feeding male Sprague-Dawley rats a synthetic diet containing 0.45% DHEA (w/w). No significant changes in total content of microsomal cytochrome P-450 or the activities of microsomal NADH-cytochrome b5 reductase and cytosolic or microsomal NAD(P)H-quinone oxidoreductase were noted at day 7 of feeding. Cytosolic glutathione S-transferase activity was decreased to 68% of control activity. Administration of DHEA p.o. or by i.p. injection for 5 days led to the same extent of induction of NADPH-cytochrome P-450 reductase activity. Maximal induction of this flavoprotein reductase was noted between days 3 and 4 of feeding or at a dose of 80-120 mg/kg i.p. A small but statistically significant increase in total microsomal cytochrome P-450 was observed after DHEA administration i.p. Rats fed DHEA had a slower growth rate compared with rats fed control diet, whereas rats treated with DHEA i.p. had growth rates identical to those of controls. The liver weights of rats given DHEA by p.o. or i.p. routes were increased significantly compared to those of control rats. Pair feeding of rats with DHA-containing or control diets served to demonstrate that the levels of induction of hepatic microsomal NADPH-cytochrome P-450 reductase and at least one form of cytochrome P450 (P-450IVA1) were the same as those seen in livers of rats fed DHEA ad libitum. This finding suggested that the induction of the flavoprotein and at least one form of the cytochrome was not due to caloric restriction. The increase in NADPH-cytochrome P-450 reductase content of liver microsomes prepared from rats either fed or treated i.p. with DHEA was also observed by Western blotting techniques. DHEA did not appear to induce any of the major forms of rat liver microsomal cytochrome P-450 that are normally increased by either phenobarbital, beta-naphthoflavone, or dexamethasone pretreatment of rats in vivo. However, the measurement of androstenedione and testosterone metabolism in vitro showed pronounced decreases in the 16 alpha-hydroxylase activities of liver microsomes following DHEA feeding.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Induction of microsomal NADPH-cytochrome P-450 reductase and cytochrome P-450IVA1 (P-450LA omega) by dehydroepiandrosterone in rats: a possible peroxisomal proliferator. 252 37

A persuasive body of evidence indicates that substantial protection against chemical carcinogenesis can be achieved by induction of enzymes concerned with the metabolism of carcinogens. There are two classes of anticarcinogenic enzyme inducers: (a) monofunctional inducers (e.g., phenolic antioxidants, isothiocyanates, coumarins, thiocarbamates, cinnamates, 1,2-dithiol-3-thiones) that elevate Phase II enzymes (such as glutathione S-transferases, NAD(P)H:quinone reductase, UDP-glucuronosyl-transferases) in various tissues without significantly raising the Phase I enzyme, aryl hydrocarbon hydroxylase (cytochrome P1-450); and (b) bifunctional inducers (e.g., polycyclic aromatic hydrocarbons, flavonoids, and azo dyes) that induce both Phase I and Phase II enzymes of xenobiotic metabolism. Induction of Phase II enzymes appears to be a sufficient condition for achieving chemoprotection, and since certain Phase I enzymes are responsible for activating carcinogens to their ultimate reactive forms, selective Phase II enzyme inducers offer intrinsically safer prospects for achieving chemoprotection. Whereas induction of both Phase I and II enzymes by bifunctional inducers depends on the Ah receptor, induction of Phase II enzymes by monofunctional inducers is independent of a functional Ah receptor. Studies on the structural requirements for induction of quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase; EC 1.6.99.2] by monofunctional inducers in Hepa 1c1c7 murine hepatoma cells have revealed that such inducers contain a distinctive chemical feature (or acquire this feature by metabolism) that regulates the synthesis of this protective enzyme. The inducers are all Michael reaction acceptors characterized by olefinic (or acetylenic) linkages that are rendered electrophilic by conjugation with electron-withdrawing groups. Typical examples are alpha, beta-unsaturated aldehydes, ketones (including quinones), thioketones, sulfones, esters, nitriles and nitro groups. The potency of these inducers parallels their reactivity as Michael acceptors. These generalizations have provided mechanistic insight into the vexing question of how so many seemingly unrelated anticarcinogens induce chemoprotective enzymes. They have also led to the prediction of entirely new and unsuspected structures of inducers, with potential for chemoprotective activity.
...
PMID:Mechanisms of induction of enzymes that protect against chemical carcinogenesis. 269 44

We have used polysomal immunoabsorption techniques to purify rat liver quinone reductase mRNA (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2, formerly called DT-diaphorase). Using the purified mRNA as template, cDNA clones complementary to quinone reductase mRNA have been constructed. One cDNA clone, pDTD55, has a 1900-base pair insert which has been demonstrated by hybrid-select translation experiments to be complementary to quinone reductase mRNA. Clone pDTD55 has been used in RNA and DNA blot hybridizations to show that quinone reductase mRNA is approximately 1900 nucleotides in length and is encoded by a gene which spans approximately 7000-8000 base pairs. We have also shown that quinone reductase mRNA is markedly elevated by 3-methylcholanthrene administration and in persistent hepatocyte nodules induced by chemical carcinogens. The elevation of quinone reductase mRNA in persistent hepatocyte nodules is not due to either gene amplification of DNA rearrangement. Rather, the quinone reductase gene is hypomethylated in persistent hepatocyte nodules compared to the gene in either liver tissue surrounding the nodule or normal liver. These data suggest that hypomethylation of specific gene sequences occurs at early stages during chemical carcinogenesis.
...
PMID:Rat liver NAD(P)H:quinone reductase. Construction of a quinone reductase cDNA clone and regulation of quinone reductase mRNA by 3-methylcholanthrene and in persistent hepatocyte nodules induced by chemical carcinogens. 300 9

The mechanisms by which 2(3)-tert-butyl-4-hydroxyanisole (BHA) protects against chemical carcinogenesis and toxicity include enhancement of the activities of several detoxification enzymes. In previous studies, 14-day administration of BHA to female CD-1 mice at 0.75% of the diet led to large increases in cytosolic glutathione transferase (EC 2.5.1.18) and reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone) (EC 1.6.99.2) [NAD(P)H:quinone reductase; DT-diaphorase] specific activities in several tissues, and elevated hepatic glutathione transferase messenger RNA. In the present study, one day of dietary BHA significantly increased NAD(P)H:quinone reductase and glutathione transferase activities in the liver, kidney, and proximal small intestine, and NAD(P)H:quinone reductase activity in the forestomach and lung. In the proximal small intestine, glutathione transferase specific activities toward 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene rose to 2.6 and 8 times those of control, respectively, and NAD(P)H:quinone reductase specific activity doubled, within 1 day on the BHA diet. Six hr after a single p.o. dose of BHA (620 mg/kg), intestinal glutathione transferase specific activities were 30 to 50% above those of control mice. In liver, the kinetics of increase of glutathione transferase messenger RNA were in accord with increased synthesis as the mechanism of elevation of glutathione transferase activity in response to BHA. Although changes in mixed-function oxygenase activities have been reported to occur more rapidly, the kinetics of the response of glutathione transferase and NAD(P)H:quinone reductase specific activities to BHA indicates that nonoxidative detoxification potential is substantially enhanced within 24 hr or less after initiation of BHA administration.
...
PMID:Kinetics of glutathione transferase, glutathione transferase messenger RNA, and reduced nicotinamide adenine dinucleotide (phosphate):quinone reductase induction by 2(3)-tert-butyl-4-hydroxyanisole in mice. 643 66

2(3)-tert-Butyl-4-hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarol-inhibited NAD(P)H:quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2] activity in mouse tissues in response to dietary administration of BHA. Cytosolic quinone reductase specific activity was increased significantly in 10 of 15 tissues examined from BHA-fed mice. The greatest proportionate increase, to 10 times control levels, was observed in liver. BHA also increased the quinone reductase activities of kidney, lung, and the mucosa of the upper small intestine severalfold. The increases of quinone reductase activities in liver and digestive tissues in response to BHA were comparable to the increases previously observed in glutathione S-transferase (EC 2.5.1.18) and epoxide hydratase (EC 3.3.2.3) activities. Quinones are among the toxic products of oxidative metabolism of aromatic hydrocarbons. NAD(P)H:quinone reductase exhibits broad specificity for structurally diverse hydrophobic quinones and may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protective effects of BHA appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the nonoxidative metabolism of a wide variety of xenobiotics.
...
PMID:Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity. 693 53

Mammalian cells have evolved elaborate mechanisms for protection against the toxic and neoplastic effects of electrophilic metabolites of carcinogens and reactive oxygen species. Phase 2 enzymes (e.g. glutathione transferase, NAD(P)H:quinone reductase, UDP-glucuronosyltransferases) and high intracellular levels of glutathione play a prominent role in providing such protection. Phase 2 enzymes are transcriptionally induced by low concentrations of a wide variety of chemical agents and such induction blocks chemical carcinogenesis. The inducers belong to many chemical classes including phenolic antioxidants. Michael reaction acceptors, isothiocyanates, 1,2-dithiole-3-thiones, trivalent arsenicals, HgCl2 and organomercurials, hydroperoxides, and vicinal dimercaptans. Induction by all classes of inducers involves the antioxidant/electrophile response element (ARE/EpRE). Inducers are widely, but unequally, distributed among edible plants. Search for such inducer activity in broccoli led to the isolation of sulforaphane, an isothiocyanate that is a very potent Phase 2 enzyme inducer and blocks mammary tumor formation in rats.
...
PMID:Chemoprotection against cancer by phase 2 enzyme induction. 859 48

Isothiocyanates occur in many edible plants and are consumed in substantial quantities by humans. A number of isothiocyanates block chemical carcinogenesis in a variety of animal models by inhibiting Phase 1 enzymes involved in carcinogen activation and by inducing Phase 2 enzymes that accelerate the inactivation of carcinogens. There are large but unexplained potency differences among individual isothiocyanates. When murine hepatoma (Hepa 1c1c7) and several other cell lines were exposed to low concentrations (1-5 microM) of certain isothiocyanates, the intracellular isothiocyanate/dithiocarbamate concentrations (measured by cyclocondensation with 1,2-benzenedithiol) rose rapidly (30 min at 37 degrees C) to very high levels (e.g., 800-900 microM). The intracellular accumulation of isothiocyanates/dithiocarbamates was temperature, structure, and glutathione dependent and could not be saturated under experimentally achievable conditions. When murine hepatoma cells were exposed to nine isothiocyanates (5 microM for 24 h at 37 degrees C) that differed considerably in structure and Phase 2 enzyme inducer potencies, the intracellular concentrations (area under curve) correlated closely and linearly with their potencies as inducers of the Phase 2 enzymes: NAD(P)H:quinone reductase and glutathione S-transferases. Isothiocyanates that did not accumulate to high levels were not inducers. These observations suggest strongly that induction of Phase 2 enzymes depends on intracellular levels of isothiocyanates/dithiocarbamates. Depletion of glutathione by treatment of Hepa cells with buthionine sulfoximine increased the inducer potencies of several isothiocyanates but could not be directly related to changes in intracellular isothiocyanate/dithiocarbamate concentrations, suggesting that glutathione may play several roles in the induction process.
...
PMID:Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes. 978 15


1 2 3 Next >>

---