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)

1. Spin-trapping techniques have been used to examine the metabolism of three xenobiotics known to produce free radicals during their metabolism. Reaction with oxygen generated superoxide, the location of which was dependent upon the xenobiotic. 2. Paraquat was metabolized by dog trachea epithelial cells under anaerobiosis to the paraquat free radical, some of which diffused into the extracellular milieu. With the addition of oxygen, superoxide was spin-trapped both intra- and extracellularly. 3. When menadione was metabolized by epithelial cells, superoxide was spin-trapped within the cell and in the surrounding media. However, in this case, extracellular superoxide arose as the result of the disproportionation reaction of menadione and menadiol, resulting from DT-diaphorase reduction of menadione followed by diffusion into extracellular space, to give the menadione semiquinone. Reduction of oxygen resulted in formation of superoxide. 4. For nitrazepam, only intracellular superoxide was generated, resulting from the one-electron reduction of this drug to its corresponding nitro anion free radical. Reaction with oxygen produced superoxide.
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PMID:Detection of free radicals as a consequence of dog tracheal epithelial cellular xenobiotic metabolism. 254 51

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.
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PMID:Mechanisms of induction of enzymes that protect against chemical carcinogenesis. 269 44

Chemically induced rat liver nodules and cancers characteristically demonstrate a limited capacity to activate xenobiotics to reactive species mainly because of decreased amounts of cytochrome P-450. These lesions also show enhancement of xenobiotic detoxication by such mechanisms as enzymic conjugation or reduction of cytotoxic species. We recently demonstrated a similar pattern of metabolic alteration in spontaneous mouse liver tumors. These findings suggested that certain phenotypic alterations attributed to chronic chemical exposure are inherent in the genetic program for carcinogenesis, and that they may arise independently of chronic exposure. To extend that study, we examined spontaneous and diethylnitrosamine-induced mouse liver tumors for nine enzyme activities commonly reported to be altered in chemically induced rat liver nodules and cancers. The activities of benzo(a)pyrene monooxygenase (EC 1.14.14.1), aminopyrene demethylase, cytochrome P-450 reductase, epoxide hydrolase (EC 3.3.2.3), and UDPglucuronosyl transferase (EC 2.4.1.17) in microsomes from spontaneous tumors relative to those from normal liver were 0.25, 0.43, 1.27, 0.90, and 0.51, respectively. Similar values were obtained with microsomes from chemically induced tumors. The activities of DT-diaphorase (EC 1.6.99.2), glutathione reductase (EC 1.6.4.2), glutathione S-transferase (EC 2.5.1.18), and glutathione peroxidase (EC 1.11.1.9) in cytosol from spontaneous tumors relative to cytosol from normal liver were 2.24, 2.0, 2.43, and 0.31, respectively. Similar values were obtained with cytosol from chemically induced tumors. These results demonstrated that a significant portion of the enzymic phenotype observed in chemically induced rat liver nodules and cancers, which may confer resistance to cytotoxic chemicals, is manifest in spontaneous and chemically induced mouse liver tumors. Further, initiated cells that exhibit this phenotype replicated and progressed in the absence of continued chemical selection.
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PMID:Xenobiotic metabolizing enzymes in genetically and chemically initiated mouse liver tumors. 308 73

DT-diaphorase (DTD) is a flavoprotein that catalyses the two-electron reduction of various redox dyes and quinones such as menadione and phylloquinone. It has been proposed that this enzyme may have a protective effect against cancer, as the two-electron reduction prevents the formation of toxic oxygen metabolites that may be generated as a result of the one-electron reduction catalysed by enzymes such as NADPH-cytochrome P-450 reductase. The effects of a purified diet supplemented with either 25% Brussels sprouts, phylloquinone (2.5 or 25 ppm) or 250 ppm indole-3-carbinol on hepatic and intestinal DTD activity in adult male Sprague-Dawley rats have been determined. One group was fed on the purified diet and dosed with 3-methylcholanthrene (20 mg/kg), 24 hr before being killed. Hepatic DTD activity was increased 3-fold in the indole-3-carbinol group, 4.4-fold in the sprouts-fed animals and 8.2-fold in the 3-methylcholanthrene-treated animals. Neither level of phylloquinone affected hepatic DTD activity. Intestinal DTD activity was increased 2.1-fold in the indole-3-carbinol group, 3.7-fold in the sprouts-fed animals and 4.3-fold in the 3-methylcholanthrene group. In animals given 25 ppm phylloquinone, intestinal enzyme activity was 60% of the control level, while no effect was noted in those given 2.5 ppm phylloquinone. Although increases in the activities of intestinal xenobiotic-metabolizing enzymes resulting from dietary influences are well documented, the increase in hepatic DTD activity seen in response to vegetable consumption has not been reported. The significance of these results in relation to the possible protective effects of dietary cruciferous vegetables against cancer is discussed.
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PMID:Dietary influences on rat hepatic and intestinal DT-diaphorase activity. 309 49

DNA is the purported target of several carcinogenic and mutagenic agents. Nuclear enzymes which could generate or detoxify reactive metabolites are of major concern. Several such enzymes have been identified within nuclei, but obtaining samples with enriched content or activity is difficult, time-consuming, and uses harsh isolation techniques. Extraction of rat liver nuclear suspensions with cholate-containing buffer results in solubilization of 25-30% of the protein. Linear extraction was obtained for total protein and cytochromes P-450 and b5, NADPH-cytochrome P-450 reductase, NADH-cytochrome b5 reductase, DT-diaphorase, and microsomal-like epoxide hydrolase with specific activities comparable to values reported for isolated nuclear membrane, while the yield was five to ten times greater. Detergent extracts of rat liver nuclei were employed to study the comparative response of microsomal and nuclear enzymes to chemical treatment. While the responses to acute inductive (phenobarbital and 3-methylcholanthrene) and toxic (carbon tetrachloride and dibromochloropropane) treatments were qualitatively similar, an initiation-promotion protocol (diethylnitrosamine with phenobarbital promotion) resulted in divergent responses between the enzymes in the two subcellular fractions. Detergent extracts of nuclei offer an efficient means of recovering xenobiotic-metabolizing enzymes from rat liver nuclei, and have been utilized to demonstrate a differential response of nuclear enzymes during preneoplastic development.
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PMID:Sodium cholate extraction of rat liver nuclear xenobiotic-metabolizing enzymes. 312 99

DT diaphorase catalyzes the transfer of two electrons to quinones to form relatively stable hydroquinones, thus protecting cells from damage by semiquinone production and subsequent superoxide radical formation. A rapid and substantial increase in the activity of DT diaphorase occurs in the cytosolic and microsomal fractions of livers of rats with Zajdela ascites hepatoma under conditions which generally depress the activity of other xenobiotic-metabolizing enzymes. The increase is time-dependent, parallels the increase in the specific activity of DT diaphorase of the growing hepatoma cells, and is limited to the liver. Treatment of rats with hepatoma cytosol results in a rapid increase in liver cytosolic DT diaphorase activity in a dose-dependent manner.
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PMID:The anticancer enzyme DT diaphorase is induced selectively in liver during ascites hepatoma growth. 312 84

The activities of UDP-glucuronyl transferase, DT-diaphorase, epoxide hydrolase, aryl hydrocarbon hydroxylase, gamma-glutamyl transferase and NADPH-cytochrome c reductase were measured in the nuclear and microsomal fractions from normal rat liver and rat liver nodules. Nodules were produced by intermittent feeding of Wistar rats with a standard diet supplemented with 0.05% (w/w) 2-acetylaminofluorene. The nuclear and microsomal fractions were isolated by differential centrifugation. The activities of UDP-glucuronyl transferase, DT-diaphorase, epoxide hydrolase and gamma-glutamyl transferase were significantly increased in the nuclear and microsomal fractions obtained from nodules as compared with normal liver. Aryl hydrocarbon hydroxylase activity was decreased in the microsomal fraction from the pathological tissue but not in the nuclear fraction. NADPH-cytochrome c reductase activity was similar in nodular and normal liver tissue. The nuclear/microsomal ratio for phase I reactions in xenobiotic metabolism was increased over normal more than two fold. Thus the nuclear and microsomal systems for drug metabolism are both changed in liver nodules. The relative enhancement of nuclear activating reactions is remarkable in the light of the increased risk for malignant transformation exhibited by nodular cells.
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PMID:Profile of drug metabolizing enzymes in the nuclear and microsomal fractions from rat liver nodules and normal liver. 324 42

Administration of a Prudhoe Bay crude oil (PBCO) to pregnant rats resulted in induction of hepatic microsomal P-450 levels and various monooxygenases in a dose-dependent manner. The activities of aniline hydroxylase, benzo[a]pyrene hydroxylase, aminopyrine-N-demethylase, ethoxyresorufin-O-deethylase, and pentoxyresorufin-O-depentylase were increased 2-3-fold, 12-15-fold, 1.4-1.8-fold, 20-24-fold, and 6-8-fold, respectively, on gestation day 18, when a single dose of PBCO (5-10 mL/kg body weight, p.o.) had been administered 24 h earlier. Glutathione-S-transferase, UDPG transferase, and DT-diaphorase activities were also increased; however, maximum induction was noticed when crude oil was given 72 h earlier. Repeated exposure (day 6-day 17, daily) of crude oil at lower levels was able to produce similar induction patterns in enzyme systems at day 18 of gestation. The xenobiotic-metabolizing enzyme systems were also induced transplacentally: treatment of pregnant rats with PBCO induced both placental and fetal hepatic enzyme systems. Liver microsomal P-450 contents, benzo[a]pyrene hydroxylase, and ethoxyresorufin-O-deethylase activities were increased 2-fold, 2-3-fold, and 10-12-fold, respectively in 18-day-old fetuses. Similar trends were noticed in placenta. Activities of phase II enzymes such as glutathione-S-transferase, UDPG transferase, and DT-diaphorase were also significantly elevated. It is suggested that crude oil induces maternal hepatic drug metabolism and that some of its constituents (mainly aromatic hydrocarbons) and (or) their metabolites pass through the placenta and thus induce drug-metabolizing enzymes transplacentally. The practical importance of the results in relation to human and environmental health is also discussed.
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PMID:Effect of a Prudhoe Bay crude oil on hepatic and placental drug metabolism in rats. 344 97

This study was performed in order to study the response of epoxide hydrolases in different subcellular compartments of mouse liver to treatment with various compounds. Male C57BL/6 mice were treated with 31 different compounds--including traditional inducers of xenobiotic-metabolizing systems, liver carcinogens, stilbene derivatives, endogenous compounds and various other drugs and xenobiotics. The effects on liver somatic index; protein contents in 'mitochondria', microsomes and cytosol prepared from the liver; epoxide hydrolase activity towards trans- or cis-stilbene oxide in these three fractions; microsomal cytochrome P-450 content; cytosolic and 'mitochondrial' glutathione transferase activity and cytosolic DT-diaphorase activity were then determined. Cytosolic epoxide hydrolase activity was induced by chlorinated paraffins, di(2-ethylhexyl)phthalate and clofibrate and depressed by alpha-naphthylisothiocyanate, 3-methylcholanthrene, benzil and quercitin. Radial immunodiffusion revealed similar changes in the amount of enzyme protein present, except for two cases, where the increase in amount was larger; and the enzyme seems to be inhibited by benzil. Microsomal epoxide hydrolase activity was induced by these same compounds and several others as well, including dibenzoylmethane, butylated hydroxyanisole and polychlorinated biphenyls. 'Mitochondrial' epoxide hydrolase activity towards trans-stilbene oxide was not affected by those compounds which induced the cytosolic enzyme, but increased about two-fold after treatment with 2-acetylaminofluorene, DL-ethionine, aflatoxin B1 and phenobarbital. There does not seem to be any co-regulation of different forms of epoxide hydrolase in mouse liver. In general small effects were observed on liver weight and protein contents in the different subcellular fractions. Polychlorinated biphenyls were the most potent of the 8 compounds which induced cytochrome P-450, while butylated hydroxyanisole induced cytosolic glutathione transferase activity to the highest extent. 'Mitochondrial' glutathione transferase activity was most induced by certain of the stilbene derivatives. The most potent inducers of DT-diaphorase activity were 3-methylcholanthrene, polychlorinated biphenyls and dinitrotoluene.
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PMID:Hepatic levels of cytosolic, microsomal and 'mitochondrial' epoxide hydrolases and other drug-metabolizing enzymes after treatment of mice with various xenobiotics and endogenous compounds. 362 71

The effects of dietary administration of equimolar doses (5 mmol/kg body wt per day) of trimethylene oxide, trimethylene sulfide, coumaran, benzofuran, indole, and indole-3-carbinol on the activities of microsomal epoxide hydrolase and several other xenobiotic metabolizing enzymes were measured in the liver of female CD-1 mouse. Every compound, with the exception of indole, caused a significant increase (P less than 0.01) of the styrene oxide epoxide hydrolase activity over controls in hepatic microsomes. These results indicate that the enzyme activity is elevated in vivo by several heterocyclic compounds with strained bond angles to a nucleophilic hetero-atom. In addition, the ability of sulfur-containing trimethylene sulfide and nitrogen-containing indole-3-carbinol to elevate the enzyme activity indicates that the heterocyclic oxygen atom is not an absolute requirement for this effect. Data from the other xenobiotic metabolizing enzymes indicate that trimethylene oxide and trimethylene sulfide enhance the epoxide hydrolase activity rather specifically, while not affecting the activities of the other enzymes measured. While the oxygen-containing coumaran and benzofuran both increased the NADH: quinone reductase activity in hepatic cytosol, the nitrogen-containing indole and indole-3-carbinol did not. This indicated a specific requirement for the oxygen atom in elevating the quinone reductase activity, which was not the case for the elevation of microsomal epoxide hydrolase activity.
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PMID:Enhancement of epoxide hydrolase activity in hepatic microsomes of mice given heterocyclic compounds. 376 53


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