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)

Two of the major cell types in bone marrow stroma, macrophages and fibroblasts, have been shown to be important regulators of both myelopoiesis and lymphopoiesis. The enzymology relating to cell-specific metabolism of phenolic metabolites of benzene in isolated mouse bone marrow stromal cells was examined. Fibroblastoid stromal cells had elevated glutathione-S-transferase (4.5-fold) and DT-diaphorase (4-fold) activity relative to macrophages, whereas macrophages demonstrated increased UDP-glucuronosyltransferase (UDP-GT, 7.5-fold) and peroxidase activity relative to stromal fibroblasts. UDP-GT and glutathione-S-transferase activities in macrophages and fibroblasts, respectively, were significantly greater than those in unpurified white marrow. Aryl sulfotransferase activity could not be detected in either bone marrow-derived macrophages or fibroblasts, and there were no significant differences in GSH content between the two cell types. Because UDP-GT activity is high in macrophages, these data suggest that DT-diaphorase levels would be rate limiting in the detoxification of benzene-derived quinones in bone marrow macrophages. The peroxidase responsible for bioactivation of benzene-derived phenolic metabolites in bone marrow macrophages is unknown but has been suggested to be prostaglandin H synthase (PGS). Hydrogen peroxide, but not arachidonic acid, supported metabolism of hydroquinone to reactive species in bone marrow-derived macrophage lysates. These data do not support a major role for PGS in peroxidase-mediated bioactivation of hydroquinone in bone marrow-derived macrophages, although PGS mRNA could be detected in these cells. Similarly, hydrogen peroxide, but not arachidonic acid, supported metabolism of hydroquinone in a human bone marrow homogenate. Peroxidase-mediated interactions between phenolic metabolites of benzene occurred in bone marrow-derived macrophages. Bioactivation of hydroquinone to species that would bind to acid-insoluble cellular macromolecules was increased by phenol and was markedly stimulated by catechol. Bioactivation of catechol was also stimulated by phenol but was inhibited by hydroquinone. These data define the enzymology and the cell-specific metabolism of benzene metabolites in bone marrow stroma and demonstrate that interactions between phenolic metabolites may contribute to the toxicity of benzene in this critical bone marrow compartment.
...
PMID:Cell-specific metabolism in mouse bone marrow stroma: studies of activation and detoxification of benzene metabolites. 148 Jan 34

The c14CoS/c14CoS mouse has a homozygous deletion of about 1.2 cM on chromosome 7 that includes the albino (c) locus. The untreated 14CoS/14CoS newborn has been reported to exhibit a marked transcriptional activation of the hepatic NAD(P)H:menadione oxidoreductase (Nmo-1; DT diaphorase; quinone reductase; azo dye reductase) gene, as well as elevated UDP glucuronosyl-transferase (UGT1*06) and glutathione transferase (GT1) activities, when compared with the cch/cch wild-type and the cch/c14CoS heterozygote. We show here that the newborn hepatic activities of seven enzymes that play a role in the oxidative stress response--NMO1, UGT1*06, GT1, copper-zinc superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase--are increased 1.5- to 25-fold in 14CoS/14CoS, as compared with ch/ch and ch/14CoS mice. The activities of four additional enzymes having no known association with the oxidative stress response--benzo[a]pyrene hydroxylase (CYP1A1, cytochrome P(1)450), acetanilide 4-hydroxylase (CYP1A2, cytochrome P(3)450), lactate dehydrogenase (LDH), and NADPH-cytochrome c reductase--are not significantly different among the three genotypes. These data suggest that there exists an "oxidative stress" response in the untreated 14CoS/14CoS newborn. We postulate that a chromosome 7 regulatory gene, which we have named Nmo-1n, might encode a trans-acting negative effector of the Nmo-1 gene, and genes corresponding to the other elevated enzymic activities described above. When both copies of Nmo-1n are deleted, as is the case in 14CoS/14CoS mice, a battery of genes involved in oxidative stress is released from negative control and becomes activated--despite the absence of any apparent oxidative insult by foreign chemicals.
...
PMID:"Oxidative stress" response in liver of an untreated newborn mouse having a 1.2-centimorgan deletion on chromosome 7. 154 Jan 61

Three indole antioxidants were compared for their efficacy to inhibit lipid peroxidation, prevent chemical hepatotoxicity and induce enzyme systems involved in the biotransformation of xenobiotics. The dietary indolyl compound indole-3-carbinol (I-3-C), and the synthetic compounds 5,10-dihydroindeno[1,2-b]-indole (DHII) and 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) inhibited carbon tetrachloride (CCl4)-initiated lipid peroxidation in rat-liver microsomes, with the order of efficacy THII greater than DHII = butylated hydroxytoluene (BHT) much greater than I-3-C. Each of the indole compounds protected isolated rat hepatocytes against toxicity by CCl4, N-methyl-N'-nitro-N-nitrosoguanidine and methylmethanesulphonate (THII congruent to DHII much greater than I-3-C). In vivo administration of the indole compounds 1 hr before treatment with CCl4 protected against hepatotoxicity (THII greater than DHII greater than I-3-C). For the enzyme induction studies, phenobarbital and beta-naphthoflavone were used as standards, with corn-oil vehicle controls. The compounds were administered by gavage at 50 mg/kg body weight/day for 10 days. I-3-C produced increases in levels of hepatic cytochromes P-450 and ethoxyresorufin O-deethylase (EROD) activity, as well as in UDP-glucuronosyl transferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GSSG-Red) and quinone reductase. I-3-C produced decreased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. DHII produced increases in EROD, UDPGT, GST, GSSG-Red and quinone reductase, with decreases in NDMA-demethylase and GSH-Px activities. The only observed effect of THII was a modest induction of EROD activity. After treatment with the indole compounds for 10 days, I-3-C enhanced, while DHII diminished, CCl4-mediated 24-hr hepatotoxicity in rats. We conclude that DHII and THII are suitable candidates to develop further as potential chemoprotective and therapeutic agents for use in humans to treat disorders involving free radicals. THII has the greater radical scavenging efficacy, whereas DHII has the greater capacity to induce many different antioxidative enzymes.
...
PMID:Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats. 187 67

Study of oxidative and non-oxidative xenobiotic-metabolizing enzymes was undertaken in microsomal and cytosolic fractions of two human livers, 10 individual and several pooled samples of human respiratory nasal mucosa obtained by surgical operation of male and female patients affected by hypertrophy of the inferior turbinates. The purity of nasal microsomes was checked by electron microscopy and marker enzyme assay. The pooled samples of respiratory nasal epithelium contained, relative to liver, a low amount of cytochrome P450 (about 25 pmol/mg protein) and associated biotransformation activities, and a low level of other components of the mixed-function oxidase system such as cytochrome b5, NADH and NADPH-cytochrome c reductase however the NADH-cytochrome b5 reductase activity was comparable to that of liver. The P450-dependent monooxygenase activities such as ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase and the dimethylnitrosamine N-demethylase were found in nearly all nasal microsomal specimens. The aniline hydroxylase and the aminopyrine or hexamethylphosphoramide N-demethylases were detected only in the pooled nasal samples. With regard to the non-oxidative enzymes, the activities of glutathione S-transferase, DT-diaphorase, epoxide hydrolase, UDP-glucuronyl-transferase, carbonyl reductase, benzaldehyde and propionaldehyde dehydrogenases, were investigated both in the individual and pooled nasal tissues and livers. These activities were similar in nasal and liver tissue, except for UDP-glucuronyltransferase which was not detected in nasal mucosa. The present findings demonstrate that the respiratory section of human nose contains a wide array of oxidative and non-oxidative enzymes, which could play a crucial role in the bioactivation or detoxication in situ of inhaled xenobiotics.
...
PMID:Xenobiotic-metabolizing enzymes in human respiratory nasal mucosa. 198 28

Indole-3-carbinol (I-3-C) and 5,10-dihydroindeno[1,2-b]indole (DHII) have been shown to be protective against carbon tetrachloride and other chemicals that cause hepatic toxicity. In part, this protection appears to be afforded by the ability of these compounds to act as antioxidants, with DHII having much the greater efficacy. In order to understand the mechanisms of chemoprotection, as well as the potential for therapeutic and pharmaceutical use in humans, the antioxidants I-3-C and DHII were examined for their intrinsic acute toxicity, and their hepatic enzyme inducing properties in mice. The results were compared with those of the well characterized agent phenobarbital. Following treatment by gavage for 10 days with 50 mg compound/kg body weight, I-3-C produced modest (10-50%) increases in hepatic cytochrome P-450, aminopyrine N-demethylase, UDP-glucuronosyl transferase (UDPGT) and glutathione S-transferase (GST), and a four-fold increase in NAD(P)H: (quinone acceptor) oxidoreductase (quinone reductase) activity. DHII did not alter oxidative enzyme activities, but increased GST and UDPGT by about 50%, and quinone reductase over five-fold. In the acute toxicity studies, DHII produced no observable 24-hr acute toxicity up to 4 g/kg body weight, except for a slight decrease in haematocrit. However, I-3-C exhibited a dose-dependent toxicity above 100 mg/kg body weight, including a decrease in hepatic reduced glutathione after 2 hr and severe neurological toxicity, and the release of liver enzymes to the plasma at 24 hr. We conclude, on the basis of the superior antioxidation efficacy of DHII, its enzyme-inducing properties, and intrinsic toxicity, that DHII or cogeners thereof have great potential as chemoprotective or therapeutic agents. However, I-3-C does not have such potential.
...
PMID:Intrinsic acute toxicity and hepatic enzyme inducing properties of the chemoprotectants indole-3-carbinol and 5,10-dihydroindeno[1,2-b]indole in mice. 204 Apr 85

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

The metabolism of hexamethylphosphoramide (HMPA), aminopyrine, ethoxycoumarin, ethoxyresorufin, and pentoxyresorufin, by the monooxygenase cytochrome P-450-dependent system, was studied in microsomes from nasal epithelial membranes and liver tissue of Sprague-Dawley rats. Nasal metabolism rates for the different substrates ranged from 9% of liver values for aminopyrine to 83% for ethoxycoumarin. HMPA-demethylase activity followed Michaelis-Menten kinetics in nasal mucosa microsomes but was biphasic in those from liver. SKF 525A, metyrapone, dioxolane and alpha-naphthoflavone (ANF), inhibitors of various P-450 monoxygenases, were examined with regard to inhibition of nasal and liver ethoxycoumarin deethylase. In addition, activity of epoxide hydrolase, glutathione S-transferase, DT-diaphorase and UDP-glucuronyltransferase (UDP-GT) in nasal tissue homogenates were investigated. These activities were generally lower than those present in the liver. Various attempts to increase the activity of oxidative enzymes in nasal tissue by PB, 3-MC and ethanol failed, 3-MC and PB doubled the microsomal UDP-GT and the epoxide hydrolase activities. The results together with data from the literature suggest that the balance between P-450 isozymes and detoxifying enzymes differs in the nose compared with the liver. The activities of these enzymes in nasal tissue of different strains of rats also varies substantially with implications regarding the metabolic fate and activation of inhaled xenobiotics.
...
PMID:Biotransformation enzymes in nasal mucosa and liver of Sprague-Dawley rats. 321 44

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.
...
PMID:Profile of drug metabolizing enzymes in the nuclear and microsomal fractions from rat liver nodules and normal liver. 324 42

1. The chemical reactivity of bromobenzene metabolite(s) responsible for its protein covalent binding was investigated by determining the effects of many chemical and enzymic probes on the metabolism and covalent binding of [3,5-3H]bromobenzene with rat liver microsomes in vitro. 2. Classical cytochrome P-450 enzyme inhibitors decreased both metabolism and binding in parallel, whereas scavenging agents for reactive oxygen species and free radicals exhibited little or no effect. Sulphur nucleophiles were extremely efficient in decreasing binding with little or no effect on metabolism. Reducing agents such as ascorbate and diaphorase decreased binding slightly more than metabolism. 3. UDP-Glucuronic acid inhibited neither metabolism nor binding, but all three mono-bromophenols decreased binding more than metabolism. Trichloropropene oxide was unique in decreasing metabolism more than binding. 4. The effects of ascorbate, glutathione, bisulphite and butylated hydroxytoluene (BHT) on metabolism and binding of five ortho-substituted bromobenzene derivatives (o-BrC6H4X; X = OCH3, CH3, Br, CF3, and CN) were similar to their effects on the metabolism and binding of bromobenzene. 5. Collectively these results support a major role for quinones as the reactive metabolites responsible for the majority of the protein covalent binding of bromobenzene and its ortho-substituted derivatives in microsomal systems in vitro.
...
PMID:Effects of chemical and enzymic probes on microsomal covalent binding of bromobenzene and derivatives. Evidence for quinones as reactive metabolites. 340 Feb 72

Anticarcinogenic enzyme inducers are of two types: (a) bifunctional inducers [2,3,7,8-tetrachlorodibenzo-p-dioxin, polycyclic aromatics, azo dyes, beta-naphthoflavone] that elevate both Phase II enzymes [e.g., glutathione S-transferases, UDP-glucuronosyltransferases, and NAD(P)H:(quinone-acceptor) oxidoreductase] and certain Phase I enzymes [e.g., aryl hydrocarbon hydroxylase (AHH)]; and (b) monofunctional inducers [e.g., diphenols, thiocarbamates, 1,2-dithiol-3-thiones, isothiocyanates] that elevate primarily Phase II enzymes without significantly affecting AHH. Since Phase I enzymes such as AHH may activate precarcinogens to ultimate carcinogens whereas Phase II enzyme induction suffices to achieve chemoprotection, an understanding of the molecular mechanisms that regulate these enzymes is critical for devising methods for chemoprotection. We report a systematic analysis of the inductions of aryl hydrocarbon hydroxylase (AHH) and NAD(P)H:quinone reductase (QR) by seven monofunctional and eight bifunctional inducers, singly or in combination, in a murine hepatoma cell line (Hepa 1c1c7) and two mutants defective in either Ah (Aryl hydrocarbon) receptor function (BPrc1) or in AHH expression (c1). We have also examined such inductions in genetically defined mouse strains with high affinity (C57BL/6J) and low affinity (DBA/2J) Ah receptors. The combination of our earlier model for the induction of Phase I and Phase II enzymes (H. J. Prochaska, M. J. De Long, and P. Talalay, Proc. Natl. Acad. Sci. USA, 82: 8232, 1985) with mechanism(s) for autoregulation of AHH (O. Hankinson, R. D. Anderson, B. W. Birren, F. Sander, M. Negishi, and D. W. Nebert, J. Biol. Chem., 260: 1790, 1985) is compatible with our results. Thus, induction of QR by monofunctional inducers does not depend on a competent Ah receptor or AHH activity and appears to involve an electrophilic chemical signal. In contrast, bifunctional inducers require competent Ah receptors to induce both AHH and QR, although the latter process appears to be regulated by more than one mechanism. It is our view that bifunctional inducers bind to the Ah receptor thereby enhancing transcription of genes encoding both AHH and QR. Metabolizable bifunctional inducers are then converted by the induced AHH to products that resemble monofunctional inducers and are capable of generating the aforementioned chemical signal. The existence of mechanism(s) for AHH autoregulation that also affect Phase II enzyme expression would account for the high basal activities of QR in the AHH-defective mutant (c1).
...
PMID:Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. 340 19


1 2 3 4 5 6 7 8 Next >>

---