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)

To exert cytotoxicity chromium VI (Cr(VI)) has to be reduced inside cells. This is achieved through both enzymatic and non-enzymatic mechanisms. Enzymatic mechanisms include DT-diaphorase, cytochrome P450, and NADPH cytochrome c reductase, and non-enzymatic mechanisms involve reduced glutathione (GSH) and ascorbic acid. The extent of cytotoxicity of Cr(VI) may thus be influenced by the availability of non-enzymatic reductants, and by the activities of the reductase enzymes. In the present paper we have investigated the effect of pretreatment with the inducing agents, phenobarbitone (PB) and 3-methylcholanthrene (3-MC), on the response of rat hepatocytes to Cr(VI). Pretreatment with PB increased the activity of NADPH cytochrome c reductase, and 3-MC increased DT-diaphorase activity in hepatocytes. Both inducers increased cytochrome P450 content, while neither influenced intracellular GSH content or the activity of glutathione reductase. Pretreatment with either PB or 3-MC resulted in amelioration of Cr(VI) toxicity both in terms of hepatocyte viability, and to a greater extent, in terms of Cr(VI) induced GSH loss. We propose that the inducing agents increase the amount of enzymatic reduction of Cr(VI) relative to non-enzymatic reduction. Thus, less GSH is used in the reduction of Cr(VI), and intracellular GSH does not fall as rapidly as in cells from control animals therefore cell integrity is better maintained. Exposure to environmental inducing agents in vivo may also alter the response of human tissues to Cr(VI).
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PMID:Pretreatment of rats with the inducing agents phenobarbitone and 3-methylcholanthrene ameliorates the toxicity of chromium (VI) in hepatocytes. 1220 17

A comparative study has been performed on populations of Unionidae from the Lake Suszek and Brda river situated in the centre of Tucholski Landscape Park, around which there are no factories and the Pilica river--affected by the influence of the nearby town agglomeration. Mussels collected from Suszek were also treated (72 h) with various concentrations of dichlorophenol (DCP; 0.1, 0.15, 0.2 ppm) and paraquat (PQ; 1, 5, 10 ppm) in laboratory conditions (aquarium). The activities of glutathione S-transferase (GST) and cytochrome P450 monooxygenase system (NAD(P)H ferricyanide reductase, NAD(P)H cytochrome c reductase), cytochrome P450 content and b(5) in microsomal and cytosolic fractions of digestive gland were investigated. The differences in enzyme activities between groups of mussels, which were exposed to various concentrations of chemical pollutants, as well as the dependence on geographical distribution in Poland, were observed. In experiments with DCP the dose-dependent increase in GST activity was found, but no changes after PQ treatment were observed. Results, in experiments with DCP and PQ, have varied from no change to increase or decrease in the measured monooxygenase activities and cytochrome P450 content. Increases have been recorded in two cases (NADPH ferricyanide reductase and cytochrome P450) after exposure to DCP and in the case of NADH ferricyanide reductase following the exposure to PQ. NAD(P)H cytochrome c reductase activity and content of P450 decreased considerably in 5 and 10 ppm PQ-treated mussels. Thus, the treatment with DCP and PQ in water changed the properties of the mussels digestive gland cytochrome P450 monooxygenase system. These changes may be used as a bioindicator, at the molecular level, of exposure to those xenobiotics not only in controlled experiments (aquaria) but also in the natural environment.
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PMID:Comparative study of the xenobiotic metabolising system in the digestive gland of the bivalve molluscs in different aquatic ecosystems and in aquaria experiments. 1229 71

NADPH diaphorase histochemical protocols were optimized for the histochemical labeling of olfactory receptor neurons (ORNs) in the nasal cavity and their axon terminals in glomeruli of the main olfactory bulb (MOB) in the Syrian hamster. This labeling was then used to map and quantify the spatial distribution of ORNs and their central projections. Diaphorase-positive ORNs were found to be rhinotopically restricted to dorsal-medially situated segments of sensory mucosa associated with central air channels in the nose, together constituting about 25% of the total receptor sheet. This topography closely resembles the zonal expression patterns of putative odorant receptor genes and cell surface glycoconjugates in the nose. Moreover, the projections of ORNs in the diaphorase-positive dorsal/central zone were found to expand onto the entire dorsal half of the MOB, consistent with spatial patterns discerned in retrograde tract-tracing studies. These boundaries indicate that dorsal/central zone ORNs project to a disproportionately larger region of the MOB than do those in the more ventral/peripheral zones. The demonstration of NADPH diaphorase activity in ORNs is inconsistent with the expression of the best-known NADPH-dependent enzymes, such as nitric oxide synthase (neuronal and endothelial isoforms) and NADPH cytochrome P450 oxidoreductase. Understanding the spatial patterning of histochemical labeling in ORNs should facilitate the biochemical identification of this diaphorase.
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PMID:NADPH diaphorase activity in olfactory receptor neurons and their axons conforms to a rhinotopically-distinct dorsal zone of the hamster nasal cavity and main olfactory bulb. 1240 2

The recently completed genome of the basidiomycete, Phanerochaete chrysosporium, revealed the presence of one NADPH-cytochrome P450 oxidoreductase (CPR; EC 1.6.2.4) gene and >123 cytochrome P450 (CYP) genes. How a single CPR can drive many CYPs is an important area of study. We have investigated this CPR to gain insight into the mechanistic and structural biodiversity of the cytochrome P450 catalytic system. Native CPR and a NH(2)-terminally truncated derivative lacking 23 amino acids have been overexpressed in Escherichia coli and purified to electrophoretic homogeneity. Steady-state kinetics of cytochrome c reductase activity revealed a random sequential bireactant kinetic mechanism in which both products form dead-end complexes reflecting differences in CPR kinetic mechanisms even within a single kingdom of life. Removal of the N-terminal anchor of P. chrysosporium CPR did not alter the kinetic properties displayed by the enzyme in vitro, indicating it was a useful modification for structural studies.
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PMID:Phanerochaete chrysosporium NADPH-cytochrome P450 reductase kinetic mechanism. 1243 68

NADPH-cytochrome P450 reductase, an obligatory component of the cytochrome P450 dependent monooxygenase system, was purified to electrophoretic homogeneity from beef liver microsomes. The purification procedure involved the ion exchange chromatography of the detergent-solubilized microsomes on first and second DEAE-cellulose columns, followed by 2',5'-ADP Sepharose affinity chromatography. Further concentration of the enzyme and removal of Emulgen 913 and 2'-AMP were accomplished on the final hydroxylapatite column. The enzyme was purified 239-fold and the yield was 13.5%. Monomer molecular weight of the enzyme was estimated to be 76000 +/- 3000 (N = 5) by SDS-PAGE. The absolute absorption spectrum of beef reductase showed two peaks at 455 and 378 nm, with a shoulder at 478 nm, characteristics of flavoproteins. The effects of cytochrome c concentration, pH, and ionic strength on enzyme activity were studied. Reduction of cytochrome c with the enzyme followed Michaelis-Menten kinetics, and the apparent K(m) of the purified enzyme was found to be 47.7 microM for cytochrome c when the enzyme activity was measured in 0.3 M potassium phosphate buffer (pH 7.7). Stability of cytochrome c reductase activity was examined at 25 and 37 degrees C in the presence and absence of 20% glycerol. The presence of glycerol enhanced the stability of cytochrome c reductase activity at both temperatures. Sheep lung microsomal cytochrome P4502B and NADPH-cytochrome P450 reductase were also purified by the already existing methods developed in our laboratory. Both beef liver and sheep lung reductases were found to be effective in supporting benzphetamine and cocaine N-demethylation reactions in the reconstituted systems containing purified sheep lung cytochrome P4502B and synthetic lipid, phosphatidylcholine dilauroyl.
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PMID:Biochemical characteristics of purified beef liver NADPH-cytochrome P450 reductase. 1248 4

The role of Kupffer cells in the hepatocellular injury and oxidative stress induced by lindane (20 mg/kg; 24h) in hyperthyroid rats (daily doses of 0.1 mg L-3,3',5-triiodothyronine (T3)/kg for three consecutive days) was assessed by the simultaneous administration of gadolinium chloride (GdCl3; 2 doses of 10mg/kg on alternate days). Hyperthyroid animals treated with lindane exhibit enhanced liver microsomal superoxide radical (O2.-) production and NADPH cytochrome c reductase activity, with lower levels of cytochrome P450, superoxide dismutase (SOD) and catalase activity, and glutathione (GSH) content over control values. These changes are paralleled by a substantial increase in the lipid peroxidation potential of the liver and in the O2.- generation/ SOD activity ratio, thus evidencing a higher oxidative stress status that correlates with the development of liver injury characterized by neutrophil infiltration and necrosis. Kupffer cell inactivation by GdCl3 suppresses liver injury in lindane/T3-treated rats with normalization of altered oxidative stress-related parameters, excepting the reduction in the content of GSH and in catalase activity. It is concluded that lindane hepatotoxicity in hyperthyroid state, that comprises an enhancement in the oxidative stress status of the liver, is largely dependent on Kupffer cell function, which may involve generation of mediators leading to pro-oxidant and inflammatory processes.
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PMID:Enhancement of lindane-induced liver oxidative stress and hepatotoxicity by thyroid hormone is reduced by gadolinium chloride. 1251 73

Drug-metabolizing enzymes play a great role in the bioactivation and also detoxification of zenobiotics and carcinogens such as N-nitrosamines and polycyclic aromatic hydrocarbons (PAHs). Therefore, the present study was undertaken to investigate the effect of narcotic drugs such as cannabis (hashish) and diacetylmorphine (heroin) on the activity of N-nitrosodimethylamine N-demethylase I [NDMA-dI], arylhydrocarbon [benzo(a)pyerne] hydroxylase [AHH], cytochrome P450 (CYP), cytochrome b(5), NADPH-cytochrome c reductase, glutathione-S-transferase, and levels of glutathione and thiobarbituric acid-reactive substances (TBARS). In addition, the present study showed the influence of hashish and heroin after single (24 h) and repeated-dose treatments (4 consecutive days) on the expression of cytochrome P450 2E1 (CYP 2E1) and cytochrome P450 2C6 (CYP 2C6). The expression of CYP 2E1 was slightly induced after single-dose and markedly induced after repeated dose-treatments of mice with hashish (10 mg kg(-1) body weight). Contrarily, heroin markedly induced the expression of CYP 2C6 after single-dose and potentially reduced this expression after repeated-dose treatments. It is believed that N-nitrosamines are activated principally by CYP 2E1 and in support of this, the activity of NDMA-dI was found to be increased after single- and repeated-dose treatments of mice with hashish by 23 and 41%, respectively. In addition, single- and repeated-dose treatments of mice with hashish increased: (1) the total hepatic content of CYP by 112 and 206%, respectively; (2) AHH activity by 110 and 165%, respectively; (3) NADPH-cytochrome c reductase activity by 21 and 98%, respectively; (4) and glutathione level by 81 and 173%, respectively. Also, single-dose treatments of mice with heroin increased the total hepatic content of CYP, AHH, NADPH-cytochrome c reductase, and glutathione level by 126, 72, 39, 205%, respectively. However, repeated dose-treatments of mice with heroin did not change such activities except cytochrome c reductase activity increased by 20%. Interestingly, the level of free radicals, TBARS, was potentially decreased after single or repeated-dose treatments with either hashish or heroin. It is clear from this study that the effects of hashish are different from those of heroin on the above mentioned enzymes particularly after repeated dose treatments. It is concluded that hashish induced the expression of CYP 2E1 and other carcinogen-metabolizing enzymes activities, and this induction could potentiate the deleterious effects of N-nitrosamines and aromatic hydrocarbons, e.g. benzo(a)pyrene, upon the liver and probably other organs. Such alterations may also change the therapeutic actions of other drugs, which are primarily metabolized by the P450 system, when administered to peoples using hashish or heroin.
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PMID:Narcotic drugs change the expression of cytochrome P450 2E1 and 2C6 and other activities of carcinogen-metabolizing enzymes in the liver of male mice. 1296 16

Transforming growth factor-beta (TGF-beta) induces an oxidative stress process in hepatocytes that mediates its apoptotic activity. To determine the cellular source of the early reactive oxygen species (ROS) generated by fetal rat hepatocytes in response to TGF-beta, we used inhibitors that block different ROS-producing systems. Diphenyleneiodonium, which inhibits NADPH oxidase and other flavoproteins, completely blocked the increase in ROS induced by TGF-beta, coincidently with an impairment of caspase-3 activation and cell death. Rotenone, an inhibitor of the NADH dehydrogenase in mitochondrial complex I, attenuated, but did not completely inhibit, ROS-production, caspase activation, and cell death mediated by TGF-beta. No significant protection was observed with inhibitors of other ROS-producing systems, such as cytochrome P450 (metyrapone), cyclooxygenase (indomethacin), and xanthine oxidase (allopurinol). Additional experiments have indicated that two different mechanisms could be involved in the early ROS production by TGF-beta. First, an inducible (cycloheximide-inhibited) NADPH oxidase-like system could account for the extramitochondrial production of ROS. Second, TGF-beta could increase ROS by a rapid downregulation of antioxidant genes. In particular, intramitochondrial ROS would increase by depletion of MnSOD. Finally, glutathione depletion is a late event and it would be more the consequence than the cause of the increase in ROS induced by TGF-beta.
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PMID:Source of early reactive oxygen species in the apoptosis induced by transforming growth factor-beta in fetal rat hepatocytes. 1473 87

The accumulation of basic drugs (cationic amphiphilic), such as beta-adrenergic antagonists, by pulmonary tissue is well known. Ring hydroxylation of nonselective beta-adrenergic blocking agent propranolol is mediated mainly by cytochrome P450 (CYP) 2D6 and N-desisopropylation by CYP1A2 in human and rat liver microsomes. In this study, the repeated administration of propranolol resulted in a marked inhibition of hepatic metabolism and an increase in its systemic availability, due to covalent binding of reactive metabolites (formed from 4-OH-propranolol) to liver microsomal P4502D enzymes. The absence of CYP1A2 and the presence of CYP2D in the lung suggest a different pulmonary metabolism of propranolol in comparison with those in the liver. In this study, we investigated its effects in vivo on some xenobiotic-metabolizing enzymes in rat type II pneumocytes (RTII) and rat alveolar macrophages (RAM). Twenty hours after the last multiple (7 days) oral administration, propranolol (100 mg/kg b.w.) decreased NADPH cytochrome c reductase activity and cytochrome P-450-dependent dealkylation of 7-benzyloxyresorufin (BROD) (CYP1A1, 2A1, 3A1) and 7-ethoxyresorufin (EROD) (CYP1A1) in RTII, while glutathione-S-transferase (GST), DT-diaphorase (QR), gamma-glutamyl transferase (gamma-GT) activities, intracellular reduced glutathione level and dealkylation of 7-pentoxyresorufin (PROD) (CYP2B1) were not changed. It was found that propranolol significantly increased NADPH cytochrome c reductase and BROD activities in RAM. The results suggest a different susceptibility of RTII and RAM to propranolol and its contrary effects on lung xenobiotic-metabolizing enzyme activities in both types of cells.
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PMID:Effects of propranolol on xenobiotic enzyme activities in rat type II pneumocytes and alveolar macrophages in vivo. 1473 27

Little is known about the effects of aging on the hepatic drug metabolizing capacity of horses despite the relatively long lifespan characterizing this species. A wide array of cytochrome P450 (CYP)-dependent monooxygenases, carboxylesterases and transferases were assayed in liver microsomes from 50 female horses in an age range between less than 1 year to over 12 years. Rather unexpectedly, both the CYP content and the activity of NADPH cytochrome c reductase rose as a function of age. Accordingly, a general increasing trend was recorded in the rate of the in vitro metabolism of the substrates reported to be related to CYP2B-, CYP2E- or CYP3A, although, as detected by Western immunoblotting, only the levels of proteins recognized by anti-rat CYP3A- and CYP2B antibodies appeared to increase consistently. Also the carboxylesterases and uridindiphosphoglucuronyl-transferase (UGT) activity toward 1-naphthol displayed a similar trend, glutathione S-transferase accepting 3,4-dichloronitrobenzene as a substrate being the only enzyme activity showing an age-related decline. A positive correlation was also found between liver cadmium content and CYP amount as well as the activities of most monooxygenases (except for those related to CYP1A), carboxylesterases, and UGT. While confirming that a number of enzyme activities are less expressed in foals, our results contradict the general view that the drug metabolizing capacity drops in elder individuals. Although several other factors can influence the kinetics of foreign compounds in aged animals, data from this study may provide insight in understanding possible age-related differences in drug efficacy and the response to toxic substances in horses.
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PMID:Postnatal development of hepatic oxidative, hydrolytic and conjugative drug-metabolizing enzymes in female horses. 1473 5


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