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)

Biotransformation in carcinogen-induced diploid and polyploid hepatocytes was studied using isozyme-selective substrates for several enzyme pathways. Diploid hepatocytes were induced by partial hepatectomy, a single injection of diethylnitrosamine, and 4 weeks of 2-acetylaminofluorene (2-AAF) feeding. Then, after an additional 3-5 weeks on the control diet, diploid and polyploid hepatocytes were separated from freshly isolated hepatocytes by centrifugal elutriation. Benzo(a)pyrene hydroxylase, ethoxyresorufin O-deethylase, and methoxycoumarin O-demethylase activities were approximately 15-40% lower in the diploid hepatocyte fraction than in the polyploid cell fraction. Activities of 1-chloro-2,4-dinitrobenzene, glutathione S-transferase, 3-hydroxy-benzo(a)pyrene or 4-hydroxybiphenyl UDP-glucuronosyltransferase, and DT-diaphorase were not different in the two cell fractions. Determination of activity during the 2-AAF treatment indicated that 2-AAF increased 7-ethoxyresorufin O-deethylase and 3-hydroxybenzo(a)pyrene glucuronosyltransferase activities by 300 and 200%, respectively, in both the diploid and polyploid hepatocyte fractions. Administration of phenobarbital for 4 days at the end of the control diet period increased ethoxyresorufin and methoxycoumarin dealkylations by 2- and 4-fold, and 3-hydroxybenzo(a)pyrene glucuronidation and 1-chloro-2,4-dinitrobenzene conjugation with glutathione by 1.5- to 2-fold in both hepatocyte fractions. Slight increases in benzo(a)pyrene hydroxylation and 4-hydroxybiphenyl glucuronidation were also evident in diploid cells. Although there is a slight decrease in cytochrome P-450-dependent monooxygenase activities, these data indicate that carcinogen-induced diploid hepatocytes do not show the typical toxicant-resistant phenotype observed in preneoplastic hepatocytes of altered liver foci, which are characterized by large decreases in monooxygenase biotransformations as well as increased activities of several phase II enzymes. This finding is compatible with the hypothesis that 2-AAF-induced nonploidizing growth of diploid hepatocytes is caused by nontoxic mechanisms in the present experimental paradigm. In addition, carcinogen-induced diploid cells respond to phenobarbital in a manner similar to that of polyploid hepatocytes.
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PMID:Biotransformation in carcinogen-induced diploid and polyploid hepatocytes separated by centrifugal elutriation. 173 74

The purpose of this study was to characterize the human cutaneous NAD(P)H: quinone reductase (NQR) activity by known inhibitors of different reductases and to compare it with the murine skin and liver NQR activity. This enzyme plays a major role in the defence of cells against oxygen stress because it inhibits the 1-electron reduction of quinones to semiquinones and their subsequent oxidation to quinones termed as quinone redox cycle. It belongs to the aromatic hydrocarbon-responsive (Ah) battery. This gene battery includes Cyp1a1 (cytochrome P-450 IA1), Cyp1a2 (cytochrome P-450 IA2) and Nmo-1 [NAD(P)H: quinone reductase]. In the skin cytochrome P-450 IA1-dependent activity is about 1-5% compared to the corresponding activity in the liver, whereas NQR has the same activity in skin and liver. NQR was determined in the cytoplasm of murine skin, liver, and human keratinocytes using 2,6-dichlorophenolindophenol as the substrate. The Ah-receptor binding compounds, such as coal tar constituents, or 3-methylcholanthrene induce cytochrome P-450-dependent activities such as aryl hydrocarbon hydroxylase or 7-ethoxyresorufin-O-de-ethylase and NQR, whereas butyl hydroxytoluol, which does not bind to the Ah receptor, induces only NQR. For inhibition studies several known inhibitors of dihydrodiol dehydrogenase, aldo-keto and carbonyl reductase activities were used. There was a similar pattern of inhibition of the basal and induced activity in all tissues investigated. Pyrazole, progesterone and phenobarbital did not inhibit, whereas dicoumarol, rutin and indomethacin inhibited NQR activity in murine skin and liver as well as in human keratinocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Induction and inhibition of NAD(P)H: quinone reductase in murine and human skin. 176 30

We have identified two regions in the 5'-flanking sequence of the rat quinone reductase gene that contain xenobiotic responsive elements. The DNA sequence of the first region spans nucleotides -393 to -352 of the 5'-flanking region and shares sequence identity with the xenobiotic responsive element (XRE) described for the cytochrome P-450 CYPIA1 gene. The DNA sequence of the second region spans nucleotides -434 to -404 of the 5'-flanking region of the quinone reductase structural gene. When a synthetic oligonucleotide corresponding to nucleotides -434 to -404 was inserted in front of a heterologous promoter linked to the chloramphenicol acetyltransferase structural gene, an increase in basal level expression as well as responsiveness to beta-naphthoflavone and t-butylhydroquinone, but not 2,3,7,8-tetrachlorodibenzo-p-dioxin, was observed. The sequence, -434 to -404, did not have any sequence identity with the XRE but shared a large degree of identity with the antioxidant responsive element recently described for the rat glutathione S-transferase Ya subunit gene (Rushmore, T. H., King, R. G., Paulson, K. E., and Pickett, C. B. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 3826-3830; Rushmore, T. H., and Pickett, C. B. (1990) J. Biol. Chem. 265, 14648-14653). These results indicate that the antioxidant responsive element can be distinguished functionally from the classical XRE and is also involved in the regulation of the quinone reductase gene by planar aromatic compounds and phenolic antioxidants.
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PMID:Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. 190 Feb 96

Modulatory effects observed due to clove administration (0.5%, 1% and 2% w/w in the diet) to Swiss albino mice for 10, 20 and 30 days in the hepatic levels of cytochrome P-450 (Cyt. P-450), cytochrome b5 (Cyt. b5), aryl hydrocarbon hydroxylase (AHH), glutathione S-transferase (GST), DT-diaphorase (DTD), acid soluble sulfhydryl (SH) content and radiation-induced malondialdehyde (MDA) formation were recorded. Enhanced GST, Cyt. b5 and SH levels were observed in all the treatment groups, excepting those maintained on a 0.5% diet for 10 days which did not show significant increase in the GST and SH levels as compared to their respective controls. Significant reduction in Cyt. P-450 and MDA levels was observed in all groups at 30 days duration. While AHH levels remained unaltered by clove administration, DTD activity was elevated by 1% and 2% clove diets at 30 days duration. An in vivo bone marrow micronucleus assay demonstrated that administration of 0.5% and 2% clove diets for 10 days neither significantly induced micronuclei nor could effectively modulate the 7, 12-dimethylbenz[a]anthracene genotoxicity in mice. The results suggest whole cloves as potential chemopreventive agents.
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PMID:Modulatory influences of clove (Caryophyllus aromaticus, L) on hepatic detoxification systems and bone marrow genotoxicity in male Swiss albino mice. 191 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.
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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

1. The t-butylquinone metabolite of BHA was shown to redox cycle with NADPH-cytochrome P-450 reductase leading to enhanced NADPH-oxidase activity for both the purified and liver microsome-bound flavoprotein. Likewise, addition of t-butylquinone (20-100 microM) strikingly inhibited electron transfer from the flavoprotein reductase to cytochrome P-450 of liver microsomes from phenobarbital-treated rats. 2. When the effect of t-butylquinone on metabolism of biphenyl was evaluated with liver microsomal fractions or isolated hepatocytes, t-butylquinone was less effective as an inhibitor then BHA alone or vitamin K3 (menadione). Addition of dicoumarol had little or no effect on the inhibitory potency of either t-butylquinone or vitamin K3 in isolated hepatocytes. 3. t-Butylquinone was not an effective reductant for exogenous oxidants, such as cytochrome c, in the presence of purified, cytosolic NAD(P)H-quinone oxidoreductase (DT-diaphorase). This property is most probably due to the lower rate of reoxidation of t-butylquinone by molecular oxygen, relative to vitamin K3 (menadione).
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PMID:The effect of the tert-butylquinone metabolite of butylated hydroxyanisole on cytochrome P-450 monooxygenase activity. 212 6

SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a novel benzotriazine di-N-oxide which shows unusually high selective toxicity towards hypoxic cells, probably as a result of reductive bioactivation. Using an HPLC assay for the parent drug and its 2- and 4-electron reduction products (SR 4317 and SR 4330, respectively), we have examined the enzymology of SR 4233 reductive metabolism in vitro using a variety of different enzyme preparations. SR 4233 was converted extremely rapidly to SR 4317 under N2 by mouse liver microsomes, and showed a marked preference for NADPH over NADH as a reduced cofactor. The reaction was inhibited completely in air and boiled preparations. It was also inhibited by 78-86% in carbon monoxide (CO), implicating cytochrome P-450 as the major microsomal SR 4233 reductase. The kinetics of reductive metabolism of SR 4233 to SR 4317 by mouse liver microsomes conformed to Michaelis-Menten kinetics, with a Km of 1.4 mM and a Vmax of 950 nmol/min/mg protein. SR 4233 reduction was also catalysed by mouse liver cytosol under N2. However, rates were markedly slower than for microsomes and showed an equal dependency on NADH and NADPH. The cytosolic enzymes aldehyde oxidase and xanthine oxidase both catalysed SR 4233 reduction to SR 4317 under N2. Purified buttermilk xanthine oxidase also catalysed this reaction. In contrast to other enzyme preparations, DT-diaphorase from Walker 256 tumour cells reduced SR 4233 predominantly to SR 4330, and this reaction occurred under aerobic conditions. These data illustrate that SR 4233 is reduced rapidly by a wide variety of reductases. We propose that the therapeutic selectivity of SR 4233 will be controlled by the relative expression of reductases in tumour versus normal tissues, and in particular by the differential participation of putative activating versus detoxifying enzymes.
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PMID:Enzymology of the reductive bioactivation of SR 4233. A novel benzotriazine di-N-oxide hypoxic cell cytotoxin. 234 70

7-Hydroxyphenoxazin-3-one, commonly known as resorufin, strongly inhibits benzo(a)pyrene-induced mutation in the Ames bacterial reversion assay. The antimutagenic mechanism is due in part to redox cycling of resorufin with the concommitant transfer of reducing equivalents from NADPH to molecular oxygen. The diversion of electrons from cytochrome P-450 enzymes results in a large decrease in the percent of benzo(a)pyrene metabolized by rat liver microsomes as measured by HPLC. Resorufin stimulated a non-stoichiometric consumption of NADPH and was reduced in S-9 or microsomal solutions. These processes were sensitive to dicumarol and NADP inhibition to different degrees in each liver fraction. This suggests two pathways are involved in resorufin redox cycling, one involving DT-diaphorase and the other with NADPH cytochrome P-450 reductase. Oxygen was shown to be an electron acceptor for S-9 mediated resorufin redox cycling, but was not consumed by a microsomal solution in the presence of resorufin and NADPH.
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PMID:Resorufin inhibits the in vitro metabolism and mutagenesis of benzo(a)pyrene. 242 85

Among naphthol derivatives tested in the Ames assay, 5,8-dihydroxy-1,4-naphthoquinone or naphthazarin was found to be the most effective inhibitor of benzo(a)pyrene mutagenicity. The inhibitory activity is due in part to the redox cycling of naphthazarin with the concommitant transfer of reducing equivalents from NADPH to molecular oxygen, thus diverting electrons from cytochrome P-450 enzymes. Metabolite separations showed a decrease in microsomal metabolism of benzo(a)pyrene and of benzo(a)pyrene-7,8-dihydrodoil upon addition of naphthazarin. Since both NADP and dicoumarol inhibited the naphthazarin-stimulated non-stoichiometric consumption of NADPH and oxygen then naphthazarin redox cycling probably involves both DT-diaphorase and NADPH cytochrome P-450 reductase.
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PMID:In vitro inhibition of the metabolism and mutagenicity of benzo(a)pyrene and benzo(a)pyrene-7,8-dihydrodiol by naphthazarin and other naphthol derivatives. 243 85

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)
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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


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