UNIPROT:Q8NEX9 - FACTA Search

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Query: UNIPROT:Q8NEX9 (reductase)
26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytochromes P450 constitute a superfamily of the phase I enzymes whose primary task is the detoxification of both endogenous and xenobiotic compounds. Fish, among non-mammalian species, have received great interest because they are a direct food source for humans as well as conveyors of toxic chemicals to human beings. The aim of the present study was the purification of the hepatic isoform of CYP1A in Prochilodus scrofa (Prochilodontidae), a Brazilian fish, using only one chromatographic step. The purification of CYP1A was done by Reverse Phase HPLC on a C18 column. Purified CYP1A was characterized with respect to electrophoretic, immunochemical and biocatalyst properties. CYP1A fractions produced a single uniform band on SDS-PAGE with an apparent molecular mass of 58 kDa. Purified CYP1A of P. scrofa showed strong cross-reactivity with antibodies directed against CYP1A from trout. The fraction was also encapsulated in two different reconstituted systems; one composed of neutral lipids and another of negatively charged lipids. In both of them, we could detect EROD activity but not PROD activity, which confirms that the CYP1A was purified with all its enzyme activity. There was an increase of activity when CYP1A and NADPH cytochrome P450 (CYP) reductase were encapsulated in negatively charged lipids, which confirms that the charge of lipid is essential to CYP1A activity. All these characteristics strongly suggest that this new procedure is efficient for purifying hepatic CYP1A from P. scrofa, showing that the CYP1A isoform of this fish has a highly conserved protein region.
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PMID:A new method to purify hepatic CYP1A of Prochilodus scrofa, a Brazilian freshwater fish. 1531 48

Administration of xenobiotics to rats results in hypercholesterolemia and in the induction of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and malic enzyme. To investigate the mechanism of the induction of the enzymes by xenobiotics, the effects of xenobiotics on gene expressions for HMG-CoA reductase, malic enzyme, and cytochrome P-450 in rat liver and in cultured hepatocyte were investigated. The treatment of rats with polychlorinated biphenyls (PCB) as a xenobiotic induced mRNAs for HMG-CoA reductase and malic enzyme as well as CYP2B1/2 (cytochrome P-450b/e). Other xenobiotics, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), and chloretone, also increased HMG-CoA reductase mRNA. In an investigation of diurnal rhythm of mRNA for HMG-CoA reductase, the induction by PCB was observed in a dark period. Induced expressions of HMG-CoA reductase gene and malic enzyme gene by PCB were observed in primary cultured rat hepatocytes and showed that the action of PCB on the gene expression relating to lipid metabolism was directed on hepatocytes. The induction was observed only in hepatocytes cultured on Engelbreth-Holm-Swarm sarcoma basement membrane gel (EHS-gel), not on type I collagen, which is usually used for monolayer culture of hepatocytes. The induction of CYP2B1/2 gene expression also was observed only in the cells cultured on EHS-gel. The induction of HMG-CoA reductase and malic enzyme by PCB required dexamethasone. However, the addition of dexamethasone per se to medium containing insulin did not show an inductive effect on levels of mRNA for HMG-CoA reductase and malic enzyme. From the data of diurnal variation and hepatocyte culture experiment, HMG-CoA reductase and malic enzyme are considered to be induced by PCB through the so-called "permissive effect" of glucocorticoid.
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PMID:Glucocorticoid-dependent induction of HMG-CoA reductase and malic enzyme gene expression by polychlorinated biphenyls in rat hepatocytes. 1553 61

This study demonstrated the occurrence of a NADPH-dependent exo-alcohol reductase in the crude membrane fraction of Candida tropicalis. Cytosolic endo-alcohol reductase activity could be separated from the membrane-bound exo-alcohol activity by means of detergent treatment, enabling the preparation of pure exo-alcohol via the enzymatic conversion of the bicyclic diketone, bicyclo[2.2.2]octane-2,6-dione. The exo-alcohol reductase is, to our knowledge, the first membrane-bound NADPH-dependent reductase accepting a xenobiotic carbonyl substrate that was not a steroid. When C. tropicalis was grown on D-sorbitol, a two-fold increase in the exo-reductase activity was observed as compared to when grown on glucose. An in silico comparison at the protein level between putative xenobiotic carbonyl reductases in Candida albicans, C. tropicalis and Saccharomyces cerevisiae was performed to explain why Candida species are often encountered when screening yeasts for novel stereoselective reduction properties. C. albicans contained more reductases with the potential to reduce xenobiotic carbonyl compounds than did S. cerevisiae. C. tropicalis had many membrane-bound reductases (predicted with the bioinformatics program, TMHMM), some of which had no counterpart in the two other organisms. The exo-reductase is suspected to be either a beta-hydroxysteroid dehydrogenase or a polyol dehydrogenase from either the short chain dehydrogenase family or the dihydroflavonol reductase family.
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PMID:Mild detergent treatment of Candida tropicalis reveals a NADPH-dependent reductase in the crude membrane fraction, which enables the production of pure bicyclic exo-alcohol. 1554 28

Juvenile visceral steatosis (jvs) mice, isolated from the C3H-H-2 degrees strain, exibit a systemic carnitine deficiency (SCD) phenotype and develop fatty liver, hyperammonemia and hypoglycemia. This phenotype is caused by a missense mutation (Leu352Arg) of a sodium-dependent carnitine/organic cation transporter, Octn2 (Slc22a5). The jvs mouse could be a useful model for pharmacokinetics and drug metabolism studies concerning Octn2 substrate drugs. In the present study, the effects of the SCD phenotype on the cytochrome P450 (P450 or CYP) dependent activities of four endobiotic and seven xenobiotic oxidations catalyzed by liver and kidney microsomes from jvs mice were investigated. The jvs-type mutation was genotyped by PCR-RFLP. The contents of total P450 and NADPH-P450 reductase were similar in the the liver microsomes from male or female mice of the wild-type and those heterozygous or homozygous for the jvs-type mutation. The 6beta-hydroxylation activities of testosterone and progesterone (marker for Cyp3a) based on the protein contents were 1.2- to 2.0-fold higher in liver microsomes from jvs/jvs-type mice compared to jvs/wt- or wt/wt-type mice. Coumarin 7-hydroxylation activities (marker for Cyp2a) were decreased to 0.7-fold in the male jvs/jvs-type mice. The activities of lauric acid 12-hydroxylation (a marker for Cyp4a) and aniline p-hydroxylation (a marker for Cyp2e1) in liver microsomes were increased 1.4- to 1.9-fold in female jvs/jvs-type mice. Genotoxic activation of 2-aminofluorene (a marker for Cyp4b1) by male and female mouse kidney microsomes were not affected by the SCD phenotype. These results demonstrated that the SCD phenotype affected the P450-dependent catalytic activities in liver microsomes. The jvs mouse could provide valuable information in drug interaction and drug metabolism studies of OCTN2 substrate drugs and new compounds in development.
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PMID:Activities of cytochrome p450 enzymes in liver and kidney microsomes from systemic carnitine deficiency mice with a gene mutation of carnitine/organic cation transporter. 1561 52

Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a "soft-nucleophile", usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics. In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences. The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.
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PMID:Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. 1592 18

A member (AKR1C19) of the aldo-keto reductase (AKR) superfamily, found by mouse genomic analysis, was shown to be highly expressed in the liver and gastrointestinal tract, but its function remains unknown. In this study, the recombinant AKR1C19 was expressed and purified to homogeneity. The enzyme was a 36-kDa monomer, and reduced alpha-dicarbonyl compounds such as camphorquinone and isatin using both NADH and NADPH as the coenzymes. Although apparent kinetic constants for the two coenzymes were similar, the NADPH-linked activity was potently inhibited by submillimolar concentrations of NAD+, but the inhibition of the NADH-linked activity was not significant, suggesting that the enzyme exhibits the NADH-linked reductase activity in vivo. AKR1C19 slowly oxidized 3-hydroxyhexobarbital, S-indan-1-ol and cis-benzene dihydrodiol, but was inactive towards steroids, prostaglandins, monosaccharides, and other xenobiotic alcohols. In addition, the enzyme was inhibited only by dicumarol, lithocholic acid and genistein of various compounds tested. Thus, AKR1C19 possesses properties distinct from other members of the AKR superfamily, and may function as a reductase for endogenous isatin and xenobiotic alpha-dicarbonyl compounds in the liver and gastrointestinal tract.
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PMID:Enzymatic properties of a member (AKR1C19) of the aldo-keto reductase family. 1593 Jul 48

Cytochrome P450 (P450) 2A6 is an important human enzyme involved in the metabolism of many xenobiotic chemicals including coumarin, indole, nicotine, and carcinogenic nitrosamines. A combination of random mutagenesis and high-throughput screening was used in the analysis of P450 2A6, utilizing a fluorescent coumarin 7-hydroxylation assay. The steady-state kinetic parameters (k(cat) and Km) for coumarin 7-hydroxylation by wild-type P450 2A6 and 35 selected mutants were measured and indicated that mutants throughout the coding region can have effects on activity. Five mutants showing decreased catalytic efficiency (k(cat)/Km) were further analyzed for substrate selectivity and binding affinities and showed reduced catalytic activities for 7-methoxycoumarin O-demethylation, tert-butyl methyl ether O-demethylation, and indole 3-hydroxylation. All mutants except one (K476E) showed decreased coumarin binding affinities (and also higher Km values), indicating that this is a major basis for the decreased enzymatic activities. A recent x-ray crystal structure of P450 2A6 bound to coumarin (Yano, J. K., Hsu, M. H., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2005) Nat. Struct. Mol. Biol. 12, 822-823) indicates that the recovered A481T and N297S mutations appear to be close to coumarin, suggesting direct perturbation of substrate interaction. The decreased enzymatic activity of the K476E mutant was associated with decreases both in NADPH oxidation and the reduction rate of the ferric P450 2A6-coumarin complex. The attenuation is caused in part to lower binding affinity for NADPH-P450 reductase, but the K476E mutant did not achieve the wild-type coumarin 7-hydroxylation activity even at high reductase concentrations.
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PMID:Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis. 1620 11

We report here the unexpected finding that recombinant or hepatic microsomal NADPH-cytochrome P450 reductase catalyzes the oxidative deformylation of a model xenobiotic aldehyde, 2-phenylpropionaldehyde, to the n-1 alcohol, 1-phenylethanol, in the absence of cytochrome P450. The flavoprotein and NADPH are absolute requirements, and the reaction displays a dependence on time and on NADPH and reductase concentration. Not surprisingly, the hydrophobic tail of the flavoprotein is not required for catalytic competence. The reductase domain of neuronal nitric oxide synthase is about 30% more active than P450 reductase, and neither flavoprotein catalyzes conversion of the aldehyde to the carboxylic acid, by far the predominant metabolite with P450s in a reconstituted system. Reductase-catalyzed deformylation is unaffected by metal ion chelators and oxygen radical scavengers, but is strongly inhibited by catalase, and the catalase-mediated inhibition is prevented by azide. These results, together with observed parallel increases in 1-phenylethanol and H(2)O(2) formation as a function of NADPH concentration, are evidence that free H(2)O(2) is rate-limiting in aldehyde deformylation by the flavoprotein reductases. This contrasts sharply with the P450-catalyzed reaction, which is brought about by iron-bound peroxide that is inaccessible to catalase.
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PMID:Oxidative aldehyde deformylation catalyzed by NADPH-cytochrome P450 reductase and the flavoprotein domain of neuronal nitric oxide synthase. 1622 17

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the interconversion of 11-oxo glucocorticoids to their 11-hydroxy metabolites, thereby controlling access of glucocorticoid hormones to the glucocorticoid receptor. Interestingly, evidence is emerging that 11beta-HSD1 fulfills an additional role in the metabolism of xenobiotic carbonyl compounds. In our studies, 11beta-HSD1 was identified as a microsomal reductase that initiates the final detoxification of xenobiotics by reducing them to alcohols that are easier to conjugate and eliminate. With its pluripotent substrate specificities for glucocorticoids and xenobiotics, 11beta-HSD1 adds to an expanding list of those hydroxysteroid dehydrogenases which, on the one hand, are capable of catalyzing the carbonyl reduction of non-steroidal carbonyl compounds, and which, on the other hand, exhibit great specificity to their physiological steroid substrates. It is conceivable that large interferences must occur between endogenous steroid metabolism and the detoxification of xenobiotic compounds on the level of hydroxysteroid dehydrogenases.
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PMID:11Beta-hydroxysteroid dehydrogenase type 1: purification from human liver and characterization as carbonyl reductase of xenobiotics. 1634 39

The present study is an effort to identify a potent chemopreventive agent against various diseases (including cancer) in which oxidative stress plays an important causative role. Here, we investigated the effect of a hydroalcoholic (80% ethanol: 20% distilled water) extract of aerial roots of Tinospora cordifolia (50 and 100mg/kg body wt./day for 2 weeks) on carcinogen/drug metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione (GSH) content, lactate dehydrogenase and lipid peroxidation in liver of 8-week-old Swiss albino mice. The modulatory effect of the extract was also examined on extrahepatic organs, i.e., lung, kidney and forestomach, for the activities of GSH S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD) and catalase. Significant increases in the levels of acid-soluble sulfhydryl (-SH) and cytochrome P(450) contents, and enzyme activities of cytochrome P(450) reductase, cytochrome b(5) reductase, GST, DTD, SOD, catalase, GSH peroxidase (GPX) and GSH reductase (GR) were observed in the liver. Both treated groups showed decreased malondialdehyde (MDA) formation. In lung SOD, catalase and GST; in kidney SOD and catalase; and in forestomach SOD, DTD and GST showed significant increase at both dose levels of treatment. BHA (0.75%, w/w in diet), a pure antioxidant compound, was used as a positive control. This group showed increase in hepatic levels of GSH content, cytochrome b(5), DTD, GST, GR and catalase, whereas MDA formation was inhibited significantly. In the BHA-treated group, the lung and kidney showed increased levels of catalase, DTD and GST, whereas SOD was significantly increased in the kidney and forestomach; the latter also showed an increase in the activities of DTD and GST. The enhanced GSH level and enzyme activities involved in xenobiotic metabolism and maintaining antioxidant status of cells are suggestive of a chemopreventive efficacy of T. cordifolia against chemotoxicity, including carcinogenicity, which warrants further investigation of active principle (s) present in the extract responsible for the observed effects employing various carcinogenesis models.
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PMID:Tinospora cordifolia induces enzymes of carcinogen/drug metabolism and antioxidant system, and inhibits lipid peroxidation in mice. 1636 Sep 36

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