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)

The induction of hepatic and intestinal cytochrome P450, NAD(P)H:quinone oxidoreductase (QOR), glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UGT) activities by intragastric administration of 1,7-phenanthroline, 2,2'-dipyridyl, and oltipraz has been investigated in rats. In the liver, all three compounds induced phase II drug-metabolizing enzymes without inducing overall cytochrome P450 concentrations and, in a direct comparison, all agents induced the enzymes to a greater extent than did the same dose of tert-butyl-4-hydroxyanisole. With a 75 mg/kg daily, 3-day regimen, UGT, GST, and QOR activities were induced by all compounds. The changes in hepatic GST, QOR, and UGT activities induced by N-heterocyclic compounds were accompanied by increases in the amounts of mRNA for GST Ya (2-2.4-fold), QOR (1.6-2.8-fold), and the UGTs UGT2B1 (4-6-fold) and UGT1A6 (4-10-fold). Changes in the amounts of UGT2B1 mRNA and UGT1A6 mRNA were highly correlated (r = 0. 9), but there was no correlation between changes in either UGT2B1 or UGT1A6 mRNA and GST Ya mRNA. No significant mRNA changes were elicited by tert-butyl-4-hydroxyanisole. Neither GST nor UGT activities were induced in the small intestinal mucosa by any agent. QOR activity was slightly induced by oltipraz. The data suggest that requirements for induction of phase II enzymes in the intestine are markedly different from requirements in the liver.
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PMID:Phase II-selective induction of hepatic drug-metabolizing enzymes by oltipraz -5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione-, 1,7-phenanthroline, and 2,2'-dipyridyl in rats is not accompanied by induction of intestinal enzymes. 945 93

We investigated the existence of an NADH-dependent paraquat (PQ) reduction system in rat liver mitochondria (Mt) in respect to the cytotoxic mechanisms of PQ. The outer membrane fractions, free from the contamination of inner membranes but with a few microsomes, catalyzed rotenone-insensitive NADH, but not NADPH, oxidation by menadione or PQ. Anti-NADH-cytochrome b5 reductase antibody and its inhibitor p-hydroxymercuribenzonate did not inhibit the NADH-PQ reduction activity. Therefore, the respiratory systems of the inner membranes and microsomal cytochrome P450 systems could not have been responsible for the reaction. Dicoumarol, an inhibitor of NAD(P)H-quinone oxidoreductase (NQO), dose dependently suppressed the NADH oxidation in the outer membrane via PQ as well as menadione, with I50 values of 190 (for menadione) and 150 microM (for PQ). Because of a lower sensitivity to NADPH and the higher doses of dicoumarol required for its inhibition, the activity in the outer membrane may be an "NADH-quinone oxidoreductase" which partly differs from the NQO previously reported. This outer membrane enzyme produced superoxide anions in the presence of both NADH and PQ and was too tightly membrane-bound to be extracted by Triton X-100 and deoxycholate. From these results, we concluded that the free radical-producing mitochondrial NADH-quinone oxidoreductase is a novel oxidation-reduction system participating in PQ toxicity. This is in good agreement with our previous results showing that PQ selectively damaged Mt in vivo and in vitro, resulting in cell death (K.-I. Hirai et al., 1992, Toxicology 72, 1-16).
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PMID:Mitochondrial NADH-quinone oxidoreductase of the outer membrane is responsible for paraquat cytotoxicity in rat livers. 950 Aug 51

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.
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PMID:Differential chemoprotection against acetaminophen-induced hepatotoxicity by latentiated L-cysteines. 981 87

1. A study of xenobiotic-metabolizing enzyme activity of the olfactory and respiratory epithelium in the pig was undertaken. The results indicated that porcine olfactory mucosa contains all the components of the P450 system. 2. Monooxygenase activities were much higher in olfactory than in respiratory microsomes, and the olfactory activities dependent on CYP2A were higher than those in the liver. By contrast, the olfactory monooxygenases associated with CYP2E1 were poorly or not detected, whereas CYP2G1 and a protein immunorelated to CYP1A2 were expressed in the olfactory epithelium. 3. The activities of several non oxidative enzymes (glutathione S-transferase, UDP-glucuronyl transferase, epoxide hydrolase, DT-diaphorase, benzaldehyde and propionaldehyde dehydrogenases, and various esterases) were also determined in porcine tissues and were found to be higher in the olfactory than in the respiratory mucosa, but lower or similar to those in liver. 4. An unexpected finding was a higher activity of olfactory UDP-GT compared with that of liver when 1-naphtol but not p-hydroxybiphenyl (a good substrate for a specific olfactory UDP-GT(olf) in bovine and rat) was used as substrate, suggesting a porcine specific expression of UDP-GT isoforms. 5. The results taken together indicate that the olfactory epithelium of mammals has a similar cytochrome P450 profile with the CYP2A and CYP2G1 as dominant isoforms, whereas the olfactory non-oxidative enzymes appear qualitatively and quantitatively expressed to different extents.
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PMID:Xenobiotic-metabolizing enzymes in pig nasal and hepatic tissues. 984 40

1. Changes in the major hepatic drug-metabolizing enzymes by compounds identified as atypical inducers (multienzyme response but devoid of cytochrome P450-inducing ability) in rat were investigated in mouse. Animals were treated with 1,7-phenanthroline, 2,2'-dipyridyl, 7,8-benzoquinoline and oltipraz at 75 and 150 mg/kg daily for 3 days. 2. UDP-glucuronosyltransferase (UGT) activities showed only limited changes, UGT activity towards 4-nitrophenol and 1-naphthol was induced by the 75 mg/kg dose of 2,2'-dipyridyl and UGT activity towards morphine was induced by 150 mg/kg doses of 7,8-benzoquinoline and oltipraz. UGT activity towards oestrone was not induced by any treatment regimen and showed a decrease following treatment with the lower dose of 7,8-benzoquinoline. 3. In contrast with the limited effect on UGT activities, glutathione S-transferase and NAD(P)H:quinone oxidoreductase activities were significantly elevated by most compounds. Glutathione S-transferase activity was significantly elevated by the 150 mg/kg dose of 1,7-phenanthroline (73%), 2,2'-dipyridyl (52%) and oltipraz (75%), and also the lower dose of 1,7-phenanthroline (47%). NAD(P)H:quinone oxidoreductase activity was significantly elevated by the higher dose of all N-heterocycles (155-323%) as well as the lower dose of 1,7-phenanthroline (180%). 4. In contrast with the effect previously seen in rat, 7,8-benzoquinoline significantly elevated mouse cytochrome P450 concentration but not 7-ethoxyresorufin O-dealkylase activity. As in rat, no N-heterocycle-containing compound significantly elevated pentoxyresorufin O-dealkylase activity. 5. Overall, mouse show a more limited response in the range of drug-metabolizing enzymes induced by N-heterocycles compared with rat, but as in rat, cytochrome P450 was largely unaffected.
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PMID:Drug-metabolizing enzyme induction by 2,2'-dipyridyl, 1,7-phenanthroline, 7,8-benzoquinoline and oltipraz in mouse. 984 42

1. The herbicides butachlor (2-chloro-2',6',diethyl-N-[buthoxymethyl] acetanilide) and pretilachlor (2-chloro-2',6'-diethyl-N-[2-propoxyethyl] acetanilide) are widely used in Asia, South America, Europe and Africa. Isoprothiolane (diisopropyl-1,3-dithiolan-2-ylidenemalonate) is used as a fungicide and an insecticide in rice paddies. We administered these agrochemicals to the male rat and examined their effects on cytochrome P450 (P450), glutathione S-transferase (GST), UDP-glucuronosyltransferase (UDPGT), and NAD(P)H-quinone oxidoreductase 1 (NQO1)-related metabolism in the liver. 2. Administration of isoprothiolane, butachlor or pretilachlor to rat induced hepatic P4502B subfamily-dependent enzyme activities (pentoxyresorufin O-depentylation and testosterone 16 beta-hydroxylation) up to 271-413% of control, which coincided with the increase in expression levels of the P4502B apoprotein. 3. Activities of GST toward 1-chloro-2,4-nitrobenzene and 3,4-dichloronitrobenzene were slightly induced (127-133% of control) in the liver of the rat treated with these pesticides. On the other hand, marked elevations of UDPGT activities toward p-nitrophenol (164-281% of control) were observed. NQO1-related metabolism (menadione reductase activity) was also induced (123-176% of control) in the liver of rat treated with these agrochemicals. 4. These results indicate that some of the agrochemicals currently in use are capable of inducing phase I and II xenobiotic-metabolizing enzyme activities in an isozyme selective manner. The induction of these activities may disrupt normal physiologic functions related to these enzymes in exposed animals.
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PMID:Effects of the agrochemicals butachlor, pretilachlor and isoprothiolane on rat liver xenobiotic-metabolizing enzymes. 987 35

Humans ingest about 1 g of flavonoids daily in their diet, and they are increasingly being associated with cytoprotective antitumour properties. The mechanism(s) responsible for these effects have not yet been elucidated but may involve interaction with xenobiotic metabolising enzymes to alter the metabolic activation of potential carcinogens. We have investigated the effect of the flavonoids, quercetin (Q), myricetin (M) and epicatechin (E) on the growth, morphology and enzyme activities of MCF7 human breast cancer cells. Of the three flavonoids studied only Q caused a decrease in cell protein content and decreased the reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium). It also inhibited protein, DNA and RNA synthesis to the greatest extent. Q and M increased intracellular reduced glutathione (GSH) content, and Q altered the morphology of the cells after 24 h exposure to 25 microM. E and Q inhibited the O-deethylation of ethoxyresorufin (EROD) catalysed by cytochrome P450 CYPIA. In contrast, M increased the EROD reaction 2-fold. Q increased the activity of DT-diaphorase, NADPH cytochrome c reductase and glutathione reductase, while E increased only NADPH cytochrome c reductase activity. The effects on enzyme activities in vitro suggest that there is not only the potential for flavonoids to alter metabolic activation of carcinogens but also of therapeutically administered drugs in vivo. We are at present investigating the synergy between anti-cancer drugs and flavonoids in terms of anti-tumour efficacy.
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PMID:The effect of the flavonoids, quercetin, myricetin and epicatechin on the growth and enzyme activities of MCF7 human breast cancer cells. 992 Apr 63

Carcinogen-DNA adducts may represent an intermediate end-point in the carcinogenic cascade and may reflect exposure to chemical carcinogens, as well as susceptibility and, ultimately, cancer risk. Interindividual variability in activity of enzymes involved in the metabolism of polycyclic aromatic hydrocarbons to mutagenic diol epoxides may predict adduct levels and, indirectly, lung cancer risk. Using 32P-postlabeling methods, the levels of bulky DNA adducts were determined in macroscopically normal bronchial tissues obtained from resected lobes of 143 Hungarian patients with lung malignancy and other pulmonary conditions. DNA from normal tissue was also evaluated for polymorphisms in cytochrome P450 2C9 (CYP2C9) at two sites, codons 144 (Arg/Cys) and 359 (Ile/Leu), for glutathione S-transferase P1 (GSTP1) at codon 105 and for NAD(P)H:quinone oxidoreductase (NQO1) at codon 187 (Pro/Ser). Using the Mann-Whitney U-test and analysis of variance, levels of adducts were evaluated in relation to variant genotypes, separately for smokers and non-smokers. As previously reported, bulky DNA adduct levels in smokers (n = 104) were estimated to be 54% higher than in non-smokers (n = 39) (8.6 +/- 4.2 versus 5.6 +/- 3.3 per 10(8) nucleotides, respectively, P < 0.01). Adduct levels were 16-29% higher in individuals with the homozygous Ile359/Ile359 CYP2C9 allele than in those heterozygous for the variant allele (Ile359/Leu359) [8.8 +/- 4.3 (n = 84) versus 7.6 +/- 3.5 (n = 20) for smokers and 5.8 +/- 3.5 (n = 32) versus 4.5 +/- 1.3 (n = 7) for non-smokers], although differences were not statistically significant. There were no clear differences in adduct levels in relation to genotypes of NQO1 or GSTP1. Although numbers of patients in this study are large in relation to many studies of carcinogen-DNA adducts, it is still possible that significant differences were not noted for polymorphisms in xenobiotic metabolizing enzymes due to relatively small numbers in stratified data.
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PMID:Analyses of bronchial bulky DNA adduct levels and CYP2C9, GSTP1 and NQO1 genotypes in a Hungarian study population with pulmonary diseases. 1035 78

Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci. We speculate that other loci that determine response to oxidative stress, such as NAD(H):quinone oxidoreductase (NQO1) are candidates. Accordingly, we assessed the association between NQO1 null and BCC numbers primarily to rank NQO1 null in a model that included genotypes already associated with BCC numbers. We found that only 14 out of 457 cases (3.1%) were NQO1 null. This frequency did not increase in cases with characteristics linked with BCC numbers including gender, skin type, a truncal lesion or more than one new BCC at any presentation (MPP). However, the mean number of BCC in NQO1*0 homozygotes was greater than in wild-type allele homozygotes and heterozygotes, although the difference was not quite significant (P = 0.06). These data reflect the link between NQO1 null and BCC numbers in the 42 MPP cases rather than the whole case group. We identified an interaction between NQO1 null and GSTT1 null that was associated with more BCC (P = 0.04), although only four cases had this combination. The relative influence of NQO1 null was studied in a multivariate model that included: (i) 241 patients in whom GSTM1 B, GSTT1 null and CYP2D6 EM genotype data were available, and (ii) 101 patients in whom these genotypes, as well as data on GSTM3, CYP1A1 and melanocyte-stimulating hormone receptor (MC1R) genotypes were available. NQO1 null (P = 0.001) and MC1R asp294/asp294 (P = 0.03) were linked with BCC numbers, and the association with CYP2D6 EM approached significance (P = 0.08). In a stepwise regression model only these genotypes were significantly associated with BCC numbers with NQO1 null being the most powerful predictor.
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PMID:Association of NAD(P)H:quinone oxidoreductase (NQO1) null with numbers of basal cell carcinomas: use of a multivariate model to rank the relative importance of this polymorphism and those at other relevant loci. 1038 95

Our recent studies have shown that vanadium, a dietary micronutrient, has an inhibitory response against experimentally induced rat liver carcinogenesis. In the present study, the effect of vanadium on hepatic xenobiotic biotransformation in rats exposed to diethylnitrosamine (DENA, 200 mg/kg, IP) was investigated to elucidate a possible mechanism of vanadium-mediated prevention of chemical carcinogenesis. Supplementary vanadium in drinking water at 0.5 parts per million (ppm) was employed ad lib before and after the intiation with DENA, before the initiation only, or during the promotional event. After 20 weeks, there was a significant reduction of hepatocyte nodules (HNs) (P<0.01), nodule multiplicity (P<0.001), and the number of nodules more than 3 mm in size in the long-term vanadium-supplemented rats than their DENA control counterparts. Total cytochrome P450 and b5 contents as well as cytochrome P450 2E1 (CYP2E1, EC 1.5.99), aryl hydrocarbon hydroxylase (AHH, EC 1.14.14.2), and UDP-glucuronyl transferase (UDPGT, EC 2.4.1.17) activities in the microsomal fractions of HNs and nonnodular surrounding parenchyma (NNSP) were found to be significantly decreased in DENA control group compared to untreated normal control. Though supplementary vanadium had little or no influence on the contents of cytochrome P450 and b5 and activities of CYP2E1 and AHH in HNs and NNSP, it substantially elevated the UDPGT activity in both HNs and NNSP liver areas. DENA treatment alone also brought about a sharp decrease in cytosolic UDP-glucose dehydrogenase (EC 1.1.1.22), DT-diaphorase (EC 1.6.99.2), and glutathione S-transferase (EC 2.5.1.18) activities in HNs and NNSP compared to normal liver. Supplementary vanadium was found to exert a marked induction in these cytosolic enzymes in HNs as well as NNSP when compared to DENA control. A positive correlation of phase I and phase II drug metabolizing enzymes in HNs or NNSP was always observed in DENA or DENA plus long-term vanadium-treated group. It is concluded that the chemoprotective effect of vanadium may be attributed to the substantial elevation of phase II conjugating enzymes, which may lead to a move and shift of the metabolic profile that may reduce the intracellular concentration of carcinogen-derived reactive intermediates.
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PMID:Characterization of selective induction and alteration of xenobiotic biotransforming enzymes by vanadium during diethylnitrosamine-induced chemical rat liver carcinogenesis. 1045 Oct 30


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