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)

As part of an ongoing study of the role of subcellular fractions on the metabolism of nitroxides, we studied the metabolism of a set of seven nitroxides in microsomes obtained from rat liver. The nitroxides were chosen to provide information on the effects of the type of charge, lipophilicity and the ring on which the nitroxide group is located. Important variables that were studied included adding NADH, adding NADPH, induction of enzymes by intake of phenobarbital and the effects of oxygen. Reduction to nonparamagnetic derivatives and oxidation back to paramagnetic derivatives were measured by electron-spin resonance spectroscopy. In general, the relative rates of reduction of nitroxides were similar to those observed with intact cells, but the effects of the various variables that were studied often differed from those observed in intact cells. The rates of reduction were very slow in the absence of added NADH or NADPH. The relative effect of these two nucleotides changed when animals were fed phenobarbital, and paralleled the levels of NADPH cytochrome c reductase, cytochrome P-450, cytochrome b5 and NADH cytochrome c reductase; results with purified NADPH-cytochrome c reductase were consistent with these results. In microsomes from uninduced animals the rate of reduction was about 10-fold higher in the absence of oxygen. The products of reduction of nitroxides by microsomes were the corresponding hydroxylamines. We conclude that there are significant NADH- and NADPH-dependent paths for reduction of nitroxides by hepatic microsomes, probably involving cytochrome c reductases and not directly involving cytochrome P-450. From this, and from parallel studies now in progress in our laboratory, it seems likely that metabolism by microsomes is an important site of reduction of nitroxides. However, mitochondrial metabolism seems to play an even more important role in intact cells.
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PMID:Metabolism of nitroxide spin labels in subcellular fraction of rat liver. I. Reduction by microsomes. 211 73

Hepatic and renal microsomal electron transport components and erythrocyte delta-aminolevulinate dehydratase were investigated in adult male rats exposed to 0, 50, 200 and 600 ppm tetrachloroethylene for 4 weeks. Body weight and liver weight showed a significant decrease only in the 600 ppm group. A dose-dependent decrease in erythrocyte delta-aminolevulinate dehydratase was observed at 200 and 600 ppm. Serum transaminase activity (SGPT) showed an increase in the 600 ppm group only. Hepatic and renal microsomal protein content showed an increase in all groups except in the kidneys of the 600 ppm group. Induction of hepatic cytochrome b5 activity was observed in all groups. However, hepatic cytochrome P-450 showed an induction and slight inhibition at 200 and 600 ppm respectively, without any alteration at 50 ppm. Renal microsomal cytochrome P-450 activity was induced in all groups. Induction of hepatic and renal NADPH cytochrome c reductase activity was observed at 600 ppm, but no alteration was seen at 50 and 200 ppm. These results indicate that chronic inhalation of tetrachloroethylene at higher levels alters mixed-function oxidase and heme metabolism.
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PMID:Chronic inhalation effects of tetrachloroethylene on hepatic and renal microsomal electron transport components and delta-aminolevulinic acid dehydratase in rats. 212 80

Hepatic ischemia induced in vivo by ligation of the left hepatic lobe of rats for up to 2 hr had no effect on cytochrome P-450, cytochrome c reductase, or lobe histology; however, cytochrome b5 increased with ischemia duration. Ethylmorphine demethylation decreased 35% after 2 hr of ischemia. Reperfusion of tissue previously made ischemic for up to 2 hr was associated with appreciable necrosis as well as decreases in cytochrome P-450, cytochrome b5, cytochrome c reductase, and ethylmorphine demethylation. Serum alanine transaminase and aspartate transaminase concentrations were increased by reperfusion of previously ischemic tissue. Reperfusion of the previously ischemic lobe for 18 hr was associated with a greater loss of cytochromes P-450 and b5, cytochrome c reductase, and ethylmorphine demethylation than reperfusion for 1 hr. The total decrease in cytochrome P-450 and b5 content was equal to the decrease in total microsomal heme content, although cytochrome P-450 decreased more than cytochrome b5. Ethoxyresorufin deethylation by hepatic microsomes from 3-methylcholanthrene-treated rats was decreased by ischemia-reperfusion; however, pentoxyresorufin dealkylation by hepatic microsomes from phenobarbital-treated rats was not, suggesting specific cytochrome P-450 isozyme loss. In vitro NADPH-dependent lipid peroxidation in hepatic microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats resulted in a selective decrease of ethoxyresorufin but not pentoxyresorufin dealkylation, similar to that observed in livers subjected to ischemia-reperfusion in vivo. These data suggest that cytochrome P-450, ethylmorphine demethylation, and ethoxyresorufin deethylation are more susceptible to ischemia-reperfusion injury than cytochrome b5 or pentoxyresorufin dealkylation.
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PMID:Effects of hepatic ischemia-reperfusion injury on the hepatic mixed function oxidase system in rats. 225 Jun 63

The purpose of this investigation was to determine age-related changes of some hepatic drug-metabolizing activities in Lacaune ewes in the foetal, neonatal (1 and 4 weeks), growing (7 months), pregnant (11 months) and adult (6 years) stages. Although microsomal cytochrome P-450 was not detected in 3-month-old foetuses, it increased regularly from 1-week- to 11-month-old animals. Among mixed-function oxidases, the development of aminopyrine and ethylmorphine N-demethylases, benzo(alpha)pyrene hydroxylase and ethoxycoumarin O-deethylase were correlated to that of total cytochrome P-450. Due to their presence in foetal liver or their more rapid evolution, cytochrome b5, NADPH cytochrome c reductase, aniline hydroxylase, benzphetamine N-demethylase and erythromycin N-demethylase did not parallel the ontogenesis of cytochrome P-450. Hepatic transferases showed different developmental patterns from mono-oxygenases, so UDP glucuronyltransferase was detected in the foetus, reached maximum activity in all young ages up to the pregnant stage and subsequently fell in adult ewes. Concerning glutathione S-transferase accepting 1-chloro-2,4-dinitrobenzene as substrate, similar values were obtained in the foetus and all young animals, whereas five- to tenfold higher values were obtained in both pregnant and adult female sheep. N-acetyltransferase using sulphamethazine did not significantly change from foetuses to adults but there were large differences in the capacity of hepatic acetylation between animals belonging to the same group.
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PMID:The development of drug-metabolizing enzymes in female sheep livers. 228 26

Adult rats of either sex and mature females ovariectomized 44 days earlier, were partially hepatectomized under ether anesthesia, leading to two-thirds organ removal. The respective controls were incised and the livers manipulated by hand. At specified p.o. periods, hepatic microsomal total protein, cytochrome P-450 and activities of the enzymes, aminopyrine demethylase and benzo[a]pyrene hydroxylase were determined for the respective pairs and submitted to analysis of variance. The data are expressed as ratios of the sham-operated to the partially hepatectomized group mean values on a percentage basis. For one male series, cytochrome P-450 and the 2 enzyme activities were significantly elevated with the intact rats at 72 and 96 h and 10 days and in yet another series of the same sex, the findings were similar except that only the cytochrome level of the controls was increased at day 10; the ratios normalized by day 21. As screened in a few groups, the changes in microsomal NADPH cytochrome c reductase were not noteworthy. Possible latency periods were shorter for the female series and the hydroxylase activity was elevated in the intact liver microsomes over test periods of 24 h to 10 days. In general, although a trend of increased parameter value for the intact group was apparent and in agreement with several published reports, statistical significance could not be substantiated in many instances, wide variations and sporadic data being encountered. None of the intact group changes in the constants were significant with the ovariectomized series. The effect of an inducer, phenobarbital, was determined in relation to the 10 day-ratios derived for males fed a casein based control diet as such and supplemented with 30 wt % each of glucose, fructose, galactose, maltose and lactose, the last one being screened only in partially hepatectomized rats. Phenobarbital was injected i.p. daily at 80 mg/kg on the last 3 days. Among other changes noted with the respective ratios, each of the intact groups displayed remarkable elevations in the total protein content. Additional comparisons are also advanced for the individual group parameter findings in relation to the control diet- and the 30% glucose-fed animals.
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PMID:Variations in microsomal parameters of intact and regenerating rat liver with time and on feeding high carbohydrate diets. 235 31

The inhibitory effect of danazol, a synthetic androgen, on the hydroxylations of testosterone as a model for endogenous steroids and the dealkylations of aminopyrine and 7-ethoxycoumarin as models for xenobiotics in mouse hepatic microsomes in vitro was studied. Danazol inhibited these enzyme activities in a dose-dependent fashion. The inhibition constants (Ki) of danazol for these enzyme activities were 1-4 orders of magnitude lower than those of cimetidine, while there was a great difference among the inhibitory potencies of danazol for each enzyme activity. Addition of danazol to microsomal preparation resulted in a reverse type I difference spectrum and the spectrophotometric analysis revealed that danazol had a high affinity for cytochrome P-450 with dissociation constants (Ks) of 0.9 and 4.2 microM, which were 2 orders of magnitude lower than those of cimetidine. On the other hand, danazol did not significantly affect reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity and levels of cytochrome P-450 in the microsomes. These results suggest that danazol is a highly potent inhibitor for several cytochrome P-450-mediated metabolisms of testosterone and xenobiotics in mouse hepatic microsomes.
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PMID:[Inhibition of cytochrome P-450-dependent monoxygenase activities by a synthetic androgen danazol in mouse hepatic microsomes]. 235 8

We have investigated a relationship between two detoxication systems, metabolic detoxication through the cytochrome P-450 (P-450) pathway and resistance to infection through interferon (IFN), in mice infected with influenza virus following exposure to coal dust (CD) and diesel exhaust (DE) particulates. Mice were exposed by inhalation to filtered air (FA; control), CD, or DE for 1 month and then inoculated intranasally (IN) with influenza virus. During infection, 7-ethoxycoumarin deethylase (7ECdeEt'ase) and ethylmorphine demethylase (EMdeMe'ase) (monooxygenases), and NADPH cytochrome c reductase (NADPH c red'ase) were measured in liver microsomes. Temporal patterns of enzyme activities were observed with control animals. EMdeMe'ase and NADPH c red'ase exhibited peak values at Day 4 postinfection (27.6 and 482 nmole/min/mg protein, respectively), compared to initial activities (9.1 and 307 nmole/min/mg protein, respectively). 7ECdeEt'ase activity decreased between Days 1-3 postvirus infection and thereafter returned to the original value (1.7 nmole/min/mg protein). When the mice were first exposed to CD or DE particulates for 1 month prior to influenza infection, changes in enzyme temporal patterns were observed. The increased EMdeMe'ase activity at Day 4 was not observed in mice exposed to CD and was reduced in mice exposed to DE. Preexposure to either particulate resulted in the abolition of the increased Day 4 activity of NADPH c red'ase. The 7ECdeEt'ase postinfection temporal pattern was not affected by a preexposure to either particulate. Estimates of the enzyme activities after the 1-month exposure to FA, CD, or DE but before virus infection indicated no changes due to particulate exposure alone. Under these conditions of particulate exposure and virus infection, serum IFN levels in the mice used in this study peaked at Days 4-5 and were unaffected by the 1-month preexposure to CD or DE (Hahon et al., (1985). The data suggest the relationship that exists between metabolic detoxication and resistance to infection in normal mice was altered during a short-term preexposure to CD or DE.
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PMID:Influenza virus-induced alterations of cytochrome P-450 enzyme activities following exposure of mice to coal and diesel particulates. 242 23

In rat hepatocytes maintained in culture, cytochrome P-450 and NADPH cytochrome c reductase activities were decreased by tunicamycin in a dose and time dependent fashion. The effect of tunicamycin was mainly due to inhibition of protein synthesis. Tunicamycin decreased L-[35S] methionine incorporation into many proteins, including a 52 kDa cytochrome P-450 isozyme. Tunicamycin also reduced RNA synthesis. These results indicate that tunicamycin decreased cytochrome P-450 levels in hepatocytes by inhibiting protein and RNA synthesis.
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PMID:Inhibition of overall protein and RNA synthesis as a mechanism for the tunicamycin induced decrease in cytochrome P-450 in rat hepatocytes. 242 61

Pituitary-determined hormones regulate the expression of hepatic cytochromes P-450 through processes involving both negative and positive controls. Accordingly, protein levels of several P-450 forms are elevated in rat liver following hypophysectomy [P-450 forms designated 2a (gene IIIA2), RLM2 (gene IIA2), and PB-4 (gene IIB1)], whereas protein levels of others are suppressed [e.g., P-450 2c (gene IIC11)]. In the present study, microsomal steroid hydroxylase activities associated with these same P-450 forms were found to be decreased by hypophysectomy, despite elevations in protein levels for several of them. Studies were, therefore, undertaken to determine the biochemical basis for this decrease in microsomal P-450 enzyme specific activity. In vivo treatment of hypophysectomized rats with gonadotropin, under conditions that restore heme to testis P-450, and heme reconstitution experiments carried out with liver homogenates indicated that a deficiency in P-450-associated heme is unlikely to account for the observed decreases in liver P-450 enzyme specific activity. Analysis of the flavoprotein P-450 reductase, however, revealed that the reductase protein and its associated cytochrome c reductase activity are decreased by 50 to 75% in liver microsomes isolated from hypophysectomized rats. Moreover, supplementation of isolated liver microsomes with exogenous purified P-450 reductase stimulated microsomal steroid hydroxylase activity preferentially in the hypophysectomized rats, to levels consistent with the observed changes in P-450 protein levels. Thus, a deficiency in P-450 reductase, which is a rate-limiting component for many P-450-dependent hydroxylation reactions, appears to be responsible for the decrease in steroid hydroxylase specific activity in the hypophysectomized rats. Although growth hormone, adrenocorticotropic hormone, and chorionic gonadotropin were each ineffective at restoring hepatic P-450 reductase when administered to hypophysectomized rats, substantial restoration of P-450 reductase levels could be achieved by treatment of the hypophysectomized rats with thyroxine. Thyroxine treatment of these rats also elevated the microsomal steroid hydroxylase activities associated with the individual hepatic P-450 forms to levels commensurate with their respective P-450 protein levels. These results establish that hepatic P-450 reductase is subject to hormonal controls that are distinct from those governing cytochrome P-450 expression and further demonstrate the complexity of endocrine control of hepatic steroid hormone metabolism.
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PMID:Hypophysectomy differentially alters P-450 protein levels and enzyme activities in rat liver: pituitary control of hepatic NADPH cytochrome P-450 reductase. 249 35

Carcinomas of the ethmoidal region of the nose are observed relatively frequently in cattle in several countries in tropical and subtropical latitudes. Viruses have been implicated as causative agents, but it has been observed that affected animals sometimes suffer from aflatoxicosis, and a role of aflatoxin B1 (AFB1) in the aetiology has also been proposed. We have examined whether the bovine nasal olfactory mucosa has a capacity to metabolize AFB1. The contents of cytochrome P-450 and cytochrome b5, and the NADPH cytochrome c reductase activity in the nasal olfactory mucosa have also been determined. Comparative experiments have been performed with the liver. Incubations with 3H-labelled AFB1 showed that the nasal olfactory mucosa has a much higher capacity than the liver to form lipid-soluble, water-soluble and tissue-bound AFB1-metabolites. High-resolution microautoradiography showed a strong localization of tissue-bound metabolites in the sustentacular cells in the apical portion of the olfactory surface epithelium and in Bowman's glands in the olfactory lamina propria mucosae. Especially in the sustentacular cells the labelling was preferentially located in the nuclei of the cells. Liquid chromatography of chloroform extracts of the nasal olfactory mucosa and the liver incubated with 3H-AFB1 showed formation of several metabolites. The dominating peak in both tissues was aflatoxin M1 (AFM1). However, the amount of AFM1 was higher in the nasal olfactory mucosa than in the liver, and the amounts and proportions of several other metabolites also differed markedly between the two tissues. The level of cytochrome P-450 in the nasal olfactory mucosa was found to be about one quarter of that in the liver, but the NADPH cytochrome c reductase activity was much higher in the nasal olfactory mucosa than in the liver. In addition, the cytochrome b5: cytochrome P-450 ratio was higher in the nasal olfactory mucosa than in the liver. The higher metabolism of AFB1 in the nasal olfactory mucosa than in the liver may be related to differences in the cytochrome P-450 isoenzyme profile. In addition, the microsomal electron transport to cytochrome P-450 may be facilitated by the high reductase: cytochrome P-450 ratio and the high cytochrome b5: cytochrome P-450 ratio in the nasal olfactory mucosa.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Metabolism of aflatoxin B1 in the bovine olfactory mucosa. 249


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