Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Enzyme systems responsible for formation of cyclopropane ring-cleavage metabolites (M1 and M2) of illudin S in rat liver were characterized. 2. The enzymes were localized in the cytosol fraction and utilized NADPH alone as electron donor; they were not affected by oxygen and had low pH optima. 3. Formation of metabolites M1 and M2 was inhibited completely by dicumarol (10(-4) M), an inhibitor of DT-diaphorase. 4. Menadione (10(-4) M) and quercetin (10(-4) M) both inhibited formation of M1 and M2 by 35% and 15%, respectively, but quinacrine, barbital, pyrazole and p-chloromercuribenzoic acid had no significant effect. 5. Results show that the enzyme systems may differ from DT-diaphorase, aldehyde oxidase, xanthine oxidase, ketone reductase, aldose reductase, aldehyde reductase and alcohol dehydrogenase, known cytosolic enzymes responsible for xenobiotic metabolism.
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PMID:Metabolism by rat liver cytosol of illudin S, a toxic substance of Lampteromyces japonicus. II. Characterization of illudin S-metabolizing enzyme. 137 39

Evidence is reported for the existence of a structurally and functionally related and probably evolutionarily conserved class of membrane-bound liver carbonyl reductases/hydroxysteroid dehydrogenases involved in steroid and xenobiotic carbonyl metabolism. Carbonyl reduction was investigated in liver microsomes of 8 vertebrate species, as well as in insect larvae total homogenate and in purified 3 alpha-hydroxysteroid dehydrogenase preparations of the procaryont Pseudomonas testosteroni, using the ketone compound 2-methyl-1,2 di-(3-pyridyl)-1-propanone (metyrapone) as substrate. The enzyme activities involved in the metyrapone metabolism were screened for their sensitivity to several steroids as inhibitors. In all fractions tested, steroids of the adrostane or pregnane class strongly inhibited xenobiotic carbonyl reduction, whereas only in the insect and procaryotic species could ecdysteroids inhibit this reaction. Immunoblot analysis with antibodies against the respective microsomal mouse liver metyrapone reductase revealed strong crossrections in all fractions tested, even in those of the insect and the procaryont. A similar crossreaction pattern was achieved when the same fractions were incubated with antibodies against 3 alpha-hydroxysteroid dehydrogenase from Pseudomonas testosteroni. The mutual immunoreactivity of the antibody species against proteins from vertebrate liver microsomes, insects and procaryonts suggests the existence of structural homologies within these carbonyl reducing enzymes. This is further confirmed by limited proteolysis of purified microsomal mouse liver carbonyl reductase and subsequent analysis of the peptide fragments with antibodies specifically purified by immunoreactivity against this respective crossreactive antigen. These immunoblot experiments revealed a 22 kDa peptide fragment which was commonly recognized by all antibodies and which might represent a conserved domain of the enzyme.
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PMID:Homologies between enzymes involved in steroid and xenobiotic carbonyl reduction in vertebrates, invertebrates and procaryonts. 147 59

Carbonyl reduction has been studied in liver, kidney, adrenal gland and ovary of female Wistar and Sprague-Dawley rats as well as of female NMRI mice by using metyrapone as a substrate and by means of direct HPLC analysis of the reduced alcohol metabolite metyrapol. Carbonyl reducing activities were found in all tissues examined so far, with that in rat ovary and adrenal gland cytosol exceeding the liver cytosolic specific activity severalfold: 15-fold and 12-fold in the Wistar strain; 12-fold and 7-fold in the Sprague-Dawley strain, respectively. In general, Wistar rat enzyme activities were about four times higher than those of Sprague-Dawley rats in all fractions, which indicates an interesting genetic difference between the two rat strains. Due to the sensitivity towards the diagnostic inhibitor quercitrin, carbonyl reductase (EC 1.1.1.184) seems to be mainly responsible for metyrapone reduction in rat and mouse adrenal gland and ovary cytosol. However, sensitivity towards dicoumarol in microsomal fractions of mouse tissues points to the involvement of further carbonyl reducing enzymes. Western blot experiments revealed immunological differences between metyrapone reductase from liver microsomes and respective enzymes of all other tissues. In conclusion, the difference in tissue and intracellular distribution suggests that several enzymes are involved in carbonyl reduction of metyrapone and the intracellular multiplicity of the enzymes may have some relation to their significance in carbonyl compound detoxification. These results support the hypothesis that carbonyl reductases, besides their participation in the metabolism of physiologically occurring substances, provide the enzymatic basis for the detoxification of xenobiotic carbonyl compounds in adrenal gland and ovary which have escaped their metabolic conversion by the liver.
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PMID:High carbonyl reductase activity in adrenal gland and ovary emphasizes its role in carbonyl compound detoxication. 151 87

Carbonyl reductase (EC 1.1.1.184) is a cytosolic, monomeric, NADPH-dependent oxidoreductase with broad specificity for carbonyl compounds and a general distribution in human tissues. A carbonyl reductase closely resembling the human enzyme is exclusively expressed in rat reproductive tissues and adrenals (Iwata, N., Inazu, N. and Satoh, T. (1989) J. Biochem. 105, 556-564). In order to investigate the relationship between the human and rat enzyme, carbonyl reductase from human testis was purified to homogeneity. The enzyme was indistinguishable from carbonyl reductase from other human tissues on the basis of physicochemical properties, substrate specificity, inhibitor sensitivity and immunological reactivity. Likewise, the human and rat testis enzymes exhibited greatly overlapping substrate specificities for prostaglandins, steroids as well as many xenobiotic carbonyl compounds, and showed the same susceptibility to inhibition by flavonoids and sulfhydryl-blocking agents. Structural homology between the two enzymes was indicated by the mutual cross-reactivity of antibodies against carbonyl reductase from one species and the enzyme protein from the other species. Unlike the rat enzyme, which is confined to Leydig cells, the human enzyme was detectable in Leydig cells as well as Sertoli and spermatogenic cells.
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PMID:Carbonyl reductase from human testis: purification and comparison with carbonyl reductase from human brain and rat testis. 154 Jun 23

3 Alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) from Pseudomonas testosteroni was shown to reduce the xenobiotic carbonyl compound metyrapone (MPON). Reversely, MPON reductase purified from mouse liver microsomes and previously characterized as aldehyde reductase, was competitively inhibited by 3 alpha-HSD steroid substrates. For MPON reduction both enzymes can use either NADH or NADPH as co-substrate. Immunoblot analysis after native and SDS gel electrophoresis of 3 alpha-HSD gave a specific crossreaction with the antibodies against the microsomal mouse liver MPON reductase pointing to structural homologies between these enzymes. In conclusion, there seem to exist structural as well as functional relationships between a mammalian liver aldehyde reductase and prokaryotic 3 alpha-HSD. Moreover, based on the molecular weights and the co-substrate specificities microsomal mouse liver MPON reductase and Pseudomonas 3 alpha-HSD seem to be members of the short-chain alcohol dehydrogenase family.
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PMID:Functional and immunological relationships between metyrapone reductase from mouse liver microsomes and 3 alpha-hydroxysteroid dehydrogenase from Pseudomonas testosteroni. 155 29

Two monomeric dihydrodiol dehydrogenases with pI values of 5.4 and 7.6 were co-purified with androsterone dehydrogenase activity to homogeneity from human liver. The two enzymes differed from each other on peptide mapping and in their heat-stabilities; with respect to the latter the dihydrodiol dehydrogenase and 3 alpha-hydroxysteroid dehydrogenase activities of the respective enzymes were similarly inactivated. The pI 5.4 enzyme was equally active towards trans- and cis-benzene dihydrodiols, and towards (S)- and (R)-forms of indan-1-ol and 1,2,3,4-tetrahydronaphth-1-ol and oxidized the 3 alpha-hydroxy group of C19-, C21- and C24-steroids, whereas the pI 7.6 enzyme showed high specificity for trans-benzene dihydrodiol, (S)-forms of the alicyclic alcohols and C19- and C21-steroids. Although the two enzymes reduced various xenobiotic carbonyl compounds and the 3-oxo group of C19- and C21-steroids, and were A-specific in the hydrogen transfer from NADPH, only the pI 5.4 enzyme showed reductase activity towards 7 alpha-hydroxy-5 beta-cholestan-3-one and dehydrolithocholic acid. The affinity of the two enzymes for the steroidal substrates was higher than that for the xenobiotic substrates. The two enzymes also showed different susceptibilities to the inhibition by anti-inflammatory drugs and bile acids. Whereas the pI-5.4 enzyme was highly sensitive to anti-inflammatory steroids, showing mixed-type inhibitions with respect to indan-1-ol and androsterone, the pI 7.6 enzyme was inhibited more potently by non-steroidal anti-inflammatory drugs and bile acids than by the steroidal drugs, and the inhibitions were all competitive. These structural and functional differences suggest that the two enzymes are 3 alpha-hydroxysteroid dehydrogenase isoenzymes.
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PMID:Structural and functional comparison of two human liver dihydrodiol dehydrogenases associated with 3 alpha-hydroxysteroid dehydrogenase activity. 155 55

The ability of brain tissue preparation to generate superoxide from xenobiotic interactions has been investigated. We showed that a significant superoxide production occurred with different molecules known to undergo a single electron reductive pathway of metabolism, both in a homogenate derived from neuronal and glial cells and in isolated cerebral microvessels which form the blood-brain barrier. Determination of the nucleotide cofactors requirement and data obtained with different subcellular fractions indicated that this production was largely associated with the microsomal fraction in a NADPH-dependent pathway and was probably mediated by NADPH-cytochrome P450 (c) reductase. A significant xenobiotic-mediated production of superoxide also occurred in mitochondria under in vitro conditions. Thus the evidence of reductive pathways of xenobiotic metabolism and the generation of oxygenated free radicals observed are of neurotoxicological significance.
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PMID:Enzyme mediated superoxide radical formation initiated by exogenous molecules in rat brain preparations. 165 70

Growth hormone (GH) may directly affect the expression of some liver cytochromes P-450 inducible by xenobiotics, but this has been difficult to establish with pituitary ablation in living animals. Therefore, we incubated adult rat hepatocytes on a laminin-rich matrix, matrigel, a new system that permits hepatocytes to respond to xenobiotics with induction of the microsomal hemoproteins, the cytochromes P-450, in culture as they do in the intact liver (Schuetz, E. G., Li, D., Omiecinski, C. J., Muller-Eberhard, U., Kleinman, H. K., Elswick, B., and Guzelian, P. S. (1988) J. Cell. Physiol. 134, 309-323). Indeed, when cultures were treated with phenobarbital, there was a rise in mRNAs for the cytochromes P-450b/e and P-450p accompanied by a rise in mRNA for 5-aminolevulinate synthase, the rate-limiting enzyme in heme biosynthesis. Analysis of nuclei from the matrigel cultures established that phenobarbital treatment had activated transcription of the P-450b/e gene. Co-incubation of the cultures with physiologic concentrations of growth hormone completely blocked the induction of these P-450 mRNAs and partially blocked the rise in 5-aminolevulinate synthase mRNA. Induction of P-450p by isosafrole also was inhibited strongly by GH, whereas P-450p induction by pregnenolone 16 alpha-carbonitrile or dexamethasone was affected only weakly by GH. The effect of GH was specific inasmuch as phenobarbital-inducible expression of P-450 reductase, glucocorticoid-inducible expression of tyrosine aminotransferase, and basal expression of albumin were unaffected by the presence or absence of growth hormone. Nuclear analysis revealed that growth hormone inhibited phenobarbital-induced P-450b/e gene transcription, whereas the hormone was without effect on transcription of the liver-specific gene, tyrosine aminotransferase. In contrast, the addition of another peptide hormone, insulin-like growth factor I, was without inhibitory effect on P-450 gene expression. We conclude that growth hormone acts specifically and selectively in direct contact with the hepatocyte to control xenobiotic induction of some liver drug-metabolizing enzymes.
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PMID:Regulation of cytochrome P-450b/e and P-450p gene expression by growth hormone in adult rat hepatocytes cultured on a reconstituted basement membrane. 168 52

The induction of specific forms of cytochrome P-450 and P-450-associated xenobiotic-metabolizing monooxygenase activities by maternal cigarette smoking was characterized in human placenta employing polyclonal and monoclonal antibodies and recombinant DNA probes. The anti-BNF-B2 (prepared against rat liver P-450 induced by beta-naphthoflavone) inhibited about 60 per cent of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase activities (ERDE) in placental tissues from smoking mothers, whereas the anti-PB-B2 (to phenobarbital-induced rat liver P-450) was without significant inhibitory effect. Inhibition of 7-ethoxycoumarin O-deethylase (ECDE) by the anti-BNF-B2 was dependent on maternal smoking: the enzyme from non-smokers was not significantly inhibited, whereas the enzyme from smokers was variably inhibited by 15-60 per cent. The monoclonal antibodies towards the major 3-methylcholanthrene-inducible and phenobarbital-inducible rat liver P-450s (Mab 1-7-1 and 2-66-3, respectively) behaved similarly, except the inhibition was somewhat stronger if present. Antibody raised against rat liver NADPH-cytochrome P-450 oxido-reductase did not inhibit any activity studied. In immunoblotting experiments, the anti-reductase recognized the protein in human placental microsomes. However, neither anti-BNF-B2, anti-PB-B2 or Mab 1-7-1 or Mab 2-66-3 detected any proteins in human placental microsomes, regardless of smoking status. Northern blot hybridization analysis of placental RNA samples showed that only P-450IA1 mRNA existed in the placentas of smoking mothers with detectable ERDE activity. Despite the discrepancy between protein blotting and immunoinhibition data all other findings support the conclusion that maternal cigarette smoking induces the expression of the CYPIA1 gene (and not CYPIA2), resulting in an increased synthesis of P-450IA1 protein and increased AHH, ERDE and ECDE activities in human placenta.
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PMID:Immunochemical and molecular biological studies on human placental cigarette smoke-inducible cytochrome P-450-dependent monooxygenase activities. 169 94

Many species within the order Actinomycetales contain one or more soluble cytochrome P450 monooxygenases, often substrate-inducible and responsible for a variety of xenobiotic transformations. The individual cytochromes exhibit a relatively broad substrate specificity, and some strains have the capacity to synthesize large amounts of the protein(s) to compensate for low catalytic turnover with some substrates. All three of the Streptomyces cytochromes sequenced to date are exclusive members of one P450 family, CYP105. In several instances, monooxygenase activity arises from induction of a P450 and associated ferredoxin, or of a P450 only, suggesting that some essential electron donor proteins (reductase and ferredoxin) are not co-ordinately regulated with the cytochrome. The overall properties of these systems suggest an adaptive strategy whose twofold purpose is to maintain a competitive advantage via the production of secondary metabolites, and, whenever possible, to utilize unusual growth substrates by introducing metabolites from these reactions into the more substrate-specific primary metabolic pathways.
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PMID:Occurrence and biological function of cytochrome P450 monooxygenases in the actinomycetes. 176 83


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