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:1.6.99.3 (diaphorase)
5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An antibody to cytochrome P450 oxidoreductase, purified from rat liver, has been used for the immunohistochemical localization of cytochrome P450 oxidoreductase-like immunoreactivity in the rat central nervous system. The distribution of this immunoreactivity has been confirmed using in situ hybridization with specific cytochrome P450 oxidoreductase antisense DNA probes. Cytochrome P450 oxidoreductase immunoreactivity was detected in neurons and was found in some glial populations. Immunoreactivity and in situ messenger RNA signals were present in many forebrain areas including the olfactory bulb, in the cerebral cortex, caudate-putamen, globus pallidus, hypothalamus, thalamus and hippocampus. Cytochrome P450 oxidoreductase was also detected in the nucleus of the posterior commissure, superior colliculus, intermediate gray layer, periaqueductal gray and in the molecular, Purkinje and granular layers of the cerebellum. In the brain stem, cytochrome P450 oxidoreductase was detected in the substantia nigra, nucleus locus coeruleus and raphe nucleus. Western blotting studies revealed the brain immunoreactive protein has a mol. wt of approximately 72,000, as reported for cytochrome P450 oxidoreductase purified from rat brain microsomes. The distribution of cytochrome P450 oxidoreductase immunoreactivity was compared with the distribution of cells exhibiting NADPH diaphorase activity, which has been established as a histochemical marker for neuronal nitric oxide synthase, an enzyme which has a C-terminus with some structural similarity with cytochrome P450 oxidoreductase and catalyses a complex reaction resulting in the synthesis of nitric oxide from arginine. In general, cytochrome P450 oxidoreductase immunoreactivity and nitric oxide synthase diaphorase activity did not co-localize; however, some neuronal populations did express nitric oxide synthase and exhibit cytochrome P450 oxidoreductase immunoreactivity. Results of immunohistochemistry and in situ hybridization experiments suggest cytochrome P450 oxidoreductase is widespread in the rat central nervous system. The distribution pattern of cytochrome P450 oxidoreductase did not match with those of any one neurotransmitter; however, it did coincide with some brain regions known to harbour central catecholaminergic neurons. The general distribution of cytochrome P450 oxidoreductase was similar to the distribution reported for haeme oxygenase 2 and several cytochrome P450 enzymes. It is possible that malfunctions in cytochrome P450 enzyme systems and/or the haeme oxygenase 2 pathways, both of which involve cytochrome P450 oxidoreductase, may have implications in neurodegenerative diseases.
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PMID:Localization of NADPH cytochrome P450 oxidoreductase in rat brain by immunohistochemistry and in situ hybridization and a comparison with the distribution of neuronal NADPH-diaphorase staining. 796 13

Female F344 rats received an i.p. injection of iron-dextran (600 mg Fe/kg) and then after 1 week were fed a diet containing 0.02% hexachlorobenzene (HCB) for up to 65 weeks. All rats (8/8) which received HCB after iron overload developed multiple hepatic nodules whereas only 3/8 rats administered HCB alone had nodules (average of one per positive liver). These hyperplastic regions were depleted of iron and were often positive for gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase P (GST-P). Telangiectasis and peliosis were prominent features in the lesions. Short-term experiments (5-15 weeks of iron/HCB treatments) showed that GGT and GST-P were induced early in the neoplastic process but not in discrete focal areas. Iron alone also caused some induction of these enzymes. Some cells with induced GST-P in either short or long term experiments also stained positively for this enzyme in the nucleus. Studies of cytochrome P450 mediated activities showed that at 5 and 15 weeks HCB had induced EROD (an estimate of CYP1A1), PROD (CYP2B1 activity) and BROD activities (CYP2B1 but also other isoenzymes). Under the influence of iron overload EROD was significantly depressed from HCB alone, but not the others or cytochrome P450 reductase. Cytosolic glutathione S-transferase activities were also induced by HCB, but, unlike microsomal EROD, preloading with iron enhanced the effects. In contrast, although cytosolic diaphorase activity was induced by HCB, this response was depressed in combination with iron. Glutathione peroxidase (with H2O2 as substrate) was depressed by both iron and HCB. Clearly, iron overload potentiates the neoplastic process induced by HCB in rats, with both enhancing and depressing effects on various enzyme activities induced by this chemical.
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PMID:Enhancement by iron of hepatic neoplasia in rats caused by hexachlorobenzene. 833 Mar 54

Complete nucleotide sequences, precise endpoints and coding potential of several 3.0-kilobase mitochondrial DNA (mtDNA) repeating units derived from two isofemale lineages of the mermithid nematode Romanomermis culicivorax have been determined. Endpoint analysis has allowed us to infer deletion and inversion events that most likely generated the present day repeat configuration. Each amplified unit contains the genes for NADH dehydrogenase subunits 3 and 6 (ND3 and ND6), an open reading frame (ORF 1) that represents a cytochrome P450-like gene, and three additional unidentified open reading frames. The primary nucleotide sequences of the R. culicivorax mt-repeat copies within individual haplotypes are highly conserved; three nearly complete copies of the repeat unit vary by 0.01% at the nucleotide level. These observations suggest that concerted evolution mechanisms may be active, resulting in sequence homogenation of these lengthy duplications.
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PMID:Molecular characterization of lengthy mitochondrial DNA duplications from the parasitic nematode Romanomermis culicivorax. 846 51

Dietary indole-3-carbinol inhibits carcinogenesis in rodents and trout. Several mechanisms of inhibition may exist. We reported previously that 3,3'-diindolylmethane, an in vivo derivative of indole-3-carbinol, is a potent noncompetitive inhibitor of trout cytochrome P450 (CYP) 1A-dependent ethoxyresorufin O-deethylase with Ki values in the low micromolar range. We now report a similar potent inhibition by 3,3'-diindolylmethane of rat and human CYP1A1, human CYP1A2, and rat CYP2B1 using various CYP-specific or preferential activity assays. 3,3'-Diindolylmethane also inhibited in vitro CYP-mediated metabolism of the ubiquitous food contaminant and potent hepatocarcinogen, aflatoxin B1. There was no inhibition of cytochrome c reductase. In addition, we found 3,3'-diindolylmethane to be a substrate for rat hepatic microsomal monooxygenase(s) and tentatively identified a monohydroxylated metabolite. These observations indicate that 3,3'-diindolylmethane can inhibit the catalytic activities of a range of CYP isoforms from lower and higher vertebrates in vitro. This broadly based inhibition of CYP-mediated activation of procarcinogens may be an indole-3-carbinol anticarcinogenic mechanism applicable to all species, including humans.
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PMID:The anticarcinogen 3,3'-diindolylmethane is an inhibitor of cytochrome P-450. 856 33

Untreated rabbit liver microsomes demonstrated the highest content of cytochrome P450 and activity of NADPH cytochrome c reductase compared to rat and monkey. The sodium dodecyl sulfate polyacrylamide gel electrophoresis of microsomes from untreated rabbit demonstrated a greater quantity of 50 KDa polypeptide than in rat and monkey. The activity of glutathione-S-transferase towards 1-chloro-2,4-dinitrobenzene and the band intensity of 26 KDa polypeptide was found to be at maximum in untreated rabbits, while rat liver demonstrated the highest activity of glutathione-S-transferase towards ethacrynic acid. The extent of hepatic microsomal lipid peroxidation was at maximum in untreated rats. The activity of catalase was higher in untreated monkeys compared to untreated rats and rabbits. Lindane at a dose of 10 mg kg-1 body weight for a period of six days increased the hepatic content of cytochrome P450 and the activities of NADPH cytochrome c reductase, aminopyrine N-demethylase, glutathione-S-transferases, haem oxygenase and lipid peroxidation, decreased non-protein thiols and concomitantly intensified the 50 and 26 KDa polypeptides in the microsomes and 100,000 x g supernatants respectively, in the rat but not in the rabbit or monkey. The results demonstrate that lindane is a bifunctional inducer in the rat and non-functional in rabbit and monkey. It also increased the activities of hepatic drug metabolizing enzymes with concomitant production of oxidative stress in the rat, whereas in rabbit and monkey it did not alter the drug metabolizing enzymes nor produced any oxidative stress.
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PMID:Differences in hepatic drug metabolizing enzymes and their response to lindane in rat, rabbit and monkey. 858 4

Solubilized NADPH-cytochrome c (P450) reductase was purified to homogeneity from an extract of spearmint (Mentha spicata) glandular trichomes by dye-ligand interaction chromatography on Matrex-Gel Red A and affinity chromatography on 2', 5'-adenosine diphosphate agarose. SDS-PAGE of the purified enzyme preparation revealed the presence of two similar proteins with masses of 82 kDa (major) and 77 kDa (minor) that crossreacted on immunoblot analysis with polyclonal antibodies directed against NADPH-cytochrome P450 reductase from Jerusalem artichoke and from mung bean. Complete immunoinhibition of reductase activity was observed with both types of polyclonal antibodies, while only partial inhibition of activity resulted using a family of monoclonal antibodies directed against the Jerusalem artichoke cytochrome P450 reductase. Inhibition of the spearmint oil gland cytochrome c reductase was also observed with the diphenyliodonium ion. The K(m) values for the cosubstrates NADPH and cytochrome c were 6.2 and 3.7 microM, respectively, and the pH optimum for activity was at 8.5. The NADPH-cytochrome c reductase reconstituted NADPH-dependent (-)-4S-limonene-6-hydroxylase activity in the presence of cytochrome P450, purified from the microsomal fraction of spearmint oil gland cells and dilauroyl phosphatidyl choline. These characteristics establish the identity of the purified enzyme as a NADPH-cytochrome P450 reductase.
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PMID:Purification and characterization of an NADPH-cytochrome P450 (cytochrome c) reductase from spearmint (Mentha spicata) glandular trichomes. 861 40

An intraperitoneal administration of PB at a daily dose of 50 mg Kg-1 body wt for 4 days increased the specific content of hepatic microsomal heme, cytochrome P450 and the activity of aminopyrine N-demethylase by 1.8, 2.8 and 3.5 fold respectively. These results were substantiated by the intensification of the 52.5 KDa polypeptide in the electrophoretogram of sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the hepatic microsomes obtained from PB-pretreated versus control macaques. PB did not affect the hepatic content of cytochrome b5 and the activity of NADPH cytochrome c reductase, whereas it decreased the activity of NADH cytochrome c reductase in the rhesus monkeys. To the best of our knowledge this is a first report on the induction of hepatic cytochrome P450 and related enzymes by PB in rhesus monkeys.
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PMID:Induction of hepatic cytochrome P450 by phenobarbitone in rhesus monkey (Macaca mulatta). 882 15

Mixed-function oxygenase (MFO) system components (cytochrome P450 and b5, "423 peak" and NADPH cytochrome c reductase) and body burdens of polycyclic aromatic hydrocarbons (PAHs) were determined seasonally in oysters, Crassostrea virginica (Gmelin 1791), collected from an undeveloped estuary (North Inlet, SC) and an urbanized estuary (Murrells Inlet, SC). All MFO system components monitored in oysters from North Inlet demonstrated seasonal variations; levels were lowest during October 1992. Whole oyster PAH tissue levels were always higher in Murrells Inlet oysters compared with North Inlet oysters. Seasonal variation of PAH body burdens was evident in oysters from Murrells Inlet; the highest levels occurred during April 1993. Differences between the two estuaries were seasonally evident in most oyster MFO system components. Reductase activity was highest at the most contaminated Murrells Inlet site during October 1992 and April 1993. This seasonal variation was positively correlated to that of their PAH body burdens. Cytochrome P450 content was also elevated at the most contaminated site during April 1993. These results suggest that reductase activity and cytochrome P450 content in Murrells Inlet oysters were induced by the high PAH body burdens during April 1993 and indicate their potential as molecular biomarkers of PAH contamination.
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PMID:Seasonal responses of the mixed-function oxygenase system in the American oyster, Crassostrea virginica (Gmelin 1791), to urban-derived polycyclic aromatic hydrocarbons. 883 82

The influence of cell density and epidermal growth factor (EGF) on the expression and inducibility of cytochrome P450 (CYP) genes of the CYP3A and CYP1A families in adult human hepatocytes in primary culture has been evaluated. Only when cultured at subconfluence and in the presence of EGF did hepatocytes exhibit a proliferative response, assessed by measuring DNA synthesis and cyclin A accumulation. In the absence of EGF, the accumulation of CYP3A4 and CYP1A2 messenger RNAs (mRNAs) in response to their respective inducers (rifampicin and dioxin) was dramatically decreased in subconfluent culture with respect to confluent cultures. The presence of EGF only slightly decreased the accumulation of these mRNAs in both confluent and subconfluent cultures. The accumulation of CYP2D6 and CYP2E1 proteins, which are constitutively expressed in confluent cultures, and the production of fibrinogen and apolipoprotein (Apo) B100 exhibited similar behavior, while nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity was affected neither by cell density nor by EGF. In contrast, the accumulation of CYP1A1 mRNA in response to dioxin was similar in confluent and subconfluent cultures, irrespective of the presence of EGF. Interestingly, CYP3A7, a gene that is preferentially expressed in the fetal liver, was expressed constitutively neither in confluent nor in subconfluent cultures, irrespective of the presence of EGF. It is concluded that the loss of cell-cell contacts rather than the proliferative status of cells per se is responsible for the dramatic decrease in the expression of CYP genes, normally expressed in the adult human liver.
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PMID:Effect of cell density and epidermal growth factor on the inducible expression of CYP3A and CYP1A genes in human hepatocytes in primary culture. 914 35

The effects of pantoprazole on xenobiotic metabolizing enzymes in rat liver microsomes were examined. Groups of female Sprague-Dawley rats were orally administered pantoprazole and other proton pump inhibitors, omeprazole and lansoprazole, at 5, 50, or 300 mg/kg/day for 7 days, followed by assays to detect changes in the levels of liver microsomal protein, cytochrome P450, cytochrome b5, NADPH cytochrome c reductase, and drug metabolizing enzyme activities. Increases in total cytochrome P450 contents were evident after a 7-day high-dose administration of all the proton pump inhibitors tested, and the increase by treatment with pantoprazole was less than that with lansoprazole. The three proton pump inhibitors increased the enzymatic activities and cytochrome P450 enzyme levels of CYP1A, CYP2B, and CYP3A. CYP1A was less induced with pantoprazole than with omeprazole or lansoprazole. In contrast, CYP2B was more strongly induced with pantoprazole than with other proton pump inhibitors. NADPH cytochrome c reductase was induced with omeprazole and pantoprazole. The present results suggest that enzyme induction differs among these proton pump inhibitors not only quantitatively but also qualitatively.
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PMID:Effects of pantoprazole on xenobiotic metabolizing enzymes in rat liver microsomes: a comparison with other proton pump inhibitors. 915 97


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