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)

Probes for cytochrome P450IVA (P450IVA), alpha- and pi-class glutathione S-transferases (GST), and phenol-metabolizing UDP-glucuronyltransferase (UDPGT-K39) detected restriction fragment length variants (RFLVs) between C57BL/6J and DBA/2J mice. These variants were used to map the P450IVA genes (Cyp4 alpha) to chromosome 4, close to Mtv-13 and Pmv-19, midway between brown (b) and Gpd-1; GST alpha genes were mapped to chromosome 9, with a cross-hybridizing sequence mapping to another chromosome; the GST pi genes were mapped to the distal end of chromosome 1 near Pmv-21; one UDPGT-K39 variant to chromosome 1, between Acrg and Emv-17, and another showed linkage to Odc-10 on an unidentified chromosome. No RFLVs were detected with probes for P450IID, P450 reductase, androsterone-metabolizing UDPGT, GST mu, or microsomal GST.
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PMID:Mapping genes encoding drug-metabolizing enzymes in recombinant inbred mice. 168 37

1. The activities of several drug-metabolizing enzymes change during the growth cycle (exponential growth to confluence) of Hep G2 cells in culture. As the rate of cell growth slowed down (days 7 to 10 after passage) the activities of ethoxy- and methoxy-resorufin O-dealkylase and of NADPH cytochrome c- and NADH cytochrome b5-reductase increased. In contrast, the O-dealkylations of pentoxy- and benzyloxy-resorufin did not change significantly during culture. 2. UDP-glucuronyltransferase activities also showed substrate-dependent alterations with time in culture. In contrast, glutathione-S-transferase activity remained constant despite a decline in the intracellular reduced glutathione content. 3. Epoxide hydrolase activity altered throughout time in culture, with an initial decrease in activity followed by a marked increase between days 7 and 10 after passage. 4. These results indicate the importance of standardizing the protocol with regard to the timing of experiments within the growth period of the cells when using hepatoma cell lines for assessing the metabolism and cytotoxicity of chemicals.
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PMID:Variation in drug-metabolizing enzyme activities during the growth of human Hep G2 hepatoma cells. 216 Nov 67

Feeding of vitamin A-deficient diet to male weanling rats for 10 weeks caused significant increase in the activities of Phase I enzyme system, i.e., cytochrome P-450, cytochrome b5 and arylhydrocarbon hydroxylase in the proximal, middle and distal segments of the intestine. Of the Phase II enzymes studied, UDP-glucuronyltransferase showed significant decrease whereas glutathione S-transferase showed significant increase. Treatment with benzo(a)pyrene caused greater induction in the levels of Phase I enzymes in deficient animals as compared to controls. In contrast to this, benzo(a)pyrene treatment induced the level of UDP-glucuronyltransferase in control rats more than in deficient rats. Intestinal NADPH cytochrome C-reductase and glutathione S-transferase remained insensitive to benzo(a)pyrene induction.
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PMID:Effects of dietary benzo(a) pyrene on intestinal phase I and phase II drug metabolizing systems in normal and vitamin A-deficient rats. 261 43

Nafimidone, a candidate anticonvulsant agent, and its metabolite (nafimidone alcohol) demonstrated potent inhibition of hepatic drug metabolism in male rats. Inhibition occurred both in vivo following acute administration as a prolongation of hexobarbital sleeping time and as an elevation of plasma hexobarbital levels, and in vitro following addition to hepatic microsomes as a disruption of ethyl-morphine N-demethylation and aniline p-hydroxylation. Inhibition of ethylmorphine N-demethylation was of a mixed type, whereas aniline p-hydroxylation was inhibited in a noncompetitive manner; the micromolar Ki values obtained for both enzymes were severalfold lower than those obtained for imidazole. Nafimidone alcohol produced a type II difference spectrum when added to rat hepatic microsomes. The Ks value was 2.1 microM. Chronic administration of nafimidone alcohol caused induction of hepatic drug metabolism typified by shortening of pentobarbital sleeping time in vivo in male mice and a doubling of hepatic microsomal cytochrome P-450 content in male rats. In rats, these changes were associated with a 30-fold elevation in the Vmax for microsomal ethoxyresorufin O-deethylase and a moderate increase in the Vmax for microsomal ethylmorphine N-demethylase, but no change in either the rate of aniline p-hydroxylation, 4-hydroxybiphenyl- or 4-methylumbelliferone UDP-glucuronosyltransferase, or the activity of the flavoprotein reductase component. These data suggest induction of a predominating cytochrome P-448-type of Phase I drug-metabolizing activity by nafimidone alcohol.
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PMID:Inhibition and induction of hepatic drug metabolism in rats and mice by nafimidone and its major metabolite nafimidone alcohol. 288 33

Male Wistar rats were dosed with miconazole, ketoconazole and itraconazole by gastric intubation once daily for up to 7 days. A dose- and time-dependent induction of the hepatic drug metabolizing enzyme system was observed for miconazole and ketoconazole, while itraconazole proved to be devoid of inductive properties even at the highest dose studied (160 mg/kg). No effect on drug metabolizing enzymes could be demonstrated for either drug at a dose level of 10 mg/kg, which is just above the antifungally active dose. At a dose of 40 mg/kg, miconazole, but not ketoconazole, significantly increased cytochrome P-450 content. At the highest dose of 160 mg/kg, both miconazole and ketoconazole increased the relative liver weight, the cytochrome P-450- and b5-content and NADPH-cyt c-reductase. Furthermore, miconazole, but not ketoconazole, increased specific microsomal aminopyrine and N,N-dimethylaniline N-demethylase activity, p-nitroanisole O-demethylase activity and UDP-glucuronyltransferase activity towards 4-nitrophenol while the specific aniline hydroxylase activity was unaffected. Ketoconazole at 160 mg/kg only induced O-demethylase activity and UDP-glucuronyltransferase activity, while it lowered the specific activities towards the other substrates. Miconazole was a relatively more potent inducer when compared to ketoconazole. Both drugs displayed biphasic effects on the mixed-function oxidase activities, which were lowered after acute administration (160 mg/kg, 1 hr before death) and were induced when determined after 23 hr had elapsed or after multiple dosage. Both drugs bound strongly to their respective induced cytochromes, giving rise to type II difference spectra, and inhibited the O-demethylase activity of the induced microsomes with an I50 of 5.2 microM for miconazole and 15.1 microM for ketoconazole. On the basis of a comparison of the enzymatic activities induced by both antimycotics with those induced by PB or 3-MC, it was concluded that miconazole behaved as a PB-type inducer, whereas ketoconazole did not belong to either category of inducers. A comparison of electrophoretograms of microsomes from different origins on SDS-PAGE revealed that miconazole increased the concentration of several proteins, whereas ketoconazole selectively induced a protein with Mr of 47,800. The protein pattern in the 50 kDa region of miconazole-induced microsomes resembled that of PB-microsomes qualitatively.
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PMID:Induction potential of antifungals containing an imidazole or triazole moiety. Miconazole and ketoconazole, but not itraconazole are able to induce hepatic drug metabolizing enzymes of male rats at high doses. 301 1

Water solubility and non-toxic properties of ascorbic acid are taken as criteria for beneficial effects of large doses of the vitamin. In the present study, male guinea pigs, dosed daily with 15, 30 or 50 mg/100g body weight for 10 weeks, demonstrated no differences in effect on liver and lung weights, body growth and microsomal protein contents of liver and lung when compared with controls. When guinea pigs were fed excessive ascorbic acid, there was a small non-significant increase (p less than 0.05) in hepatic and pulmonary cytochrome P-450, and significant increase (p less than 0.05) in hepatic cytochrome b5 which was accompanied with a significant increase in arylhydrocarbon hydroxylase activity in the two organs. Activity of NADPH-dependent cytochrome c-reductase was decreased in liver and remained unaffected in lung and colon. Drug detoxifying enzymes responded in different ways to increased intake of ascorbic acid. Activity of UDP-glucuronyltransferase remained unchanged on feeding excessive ascorbic acid, whereas glutathione S-transferase was decreased significantly in liver and was unaltered in lung and colon. Reduced glutathione was decreased only in the lung. The observed changes in drug activating and detoxifying enzymes appear to be important from drug pharmacokinetics and carcinogenesis point of view.
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PMID:Effect of large doses of ascorbic acid on the hepatic and extra-hepatic drug-metabolizing enzymes in guinea pig. 380 Oct 39

The ontogeny and endocrine regulation of sex-differentiated hepatic metabolism is mediated via the hypothalamic-pituitary axis. Using in vitro-in vivo systems, we demonstrate alterations in activity levels of six sex-differentiated enzyme systems in male rats bearing ectopic pituitary tumors after the injection of a pituitary cell line, C811RAP. Activity levels of hepatic glutathione S-transferase, UDP-glucuronyltransferase, and aryl hydrocarbon hydroxylase are reduced to activity levels of control females, while histidase, 5 alpha-reductase, and serum cholinesterase levels are increased to levels of control females, i.e. feminization of all of these enzymes. RIAs of testosterone, estrogen, FSH, and PRL are similar in tumor-bearing and control animals, but GH levels are significantly higher in tumor-bearing animals than in the controls. It is suggested that GH may be the pituitary factor responsible for the expression of sex-differentiated hepatic metabolism.
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PMID:Modulation (feminization) of hepatic enzymes by an ectopic pituitary tumor. 392 55

This article is a summary of laboratory methods for the hepatic drug metabolizing enzymes which are reliable, sensitive, and reasonably straightforward to perform. Assay conditions are given for which the enzyme rate determinations are linear with respect to time and protein concentration for hepatic tissue preparations from Charles River Sprague Dawley CD male rats. In selecting these particular assay methods, factors such as disposal of radioactive wastes, safety of laboratory personnel, and cost of required equipment were considered. Thus 9 of the 10 hepatic parameters utilize simple spectrophotometric techniques; the remaining assay (ethoxyresorufin O-deethylase) requires a spectrophotofluorometer. The hepatic toxification/detoxification assays are cytochrome P-450 and reduced glutathione content, NADPH-cytochrome C reductase, aminopyrine N-demethylase, ethoxyresorufin O-deethylase, glutathione S-transferase (3 substrates) and UDP-glucuronyltransferase (2 substrates).
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PMID:Laboratory methods for ten hepatic toxification/detoxification parameters. 642 71

We studied the effects of semisynthetic (elemental) diets on the function and morphology of the human small intestine. The enzymatic capacity of the intestinal mucosa to metabolize lipophilic xenobiotics was investigated using jejunal biopsy specimens from 15 normal subjects who were on an isocaloric, nutritionally balanced semisynthetic diet for 7 days and thereafter on a normal home diet. Each subject underwent biopsy twice: on day 7 of semisynthetic diet and again on home diet 2-6 wk later. The jejunal mucosal tissue was examined by histologic morphometry and stereomicroscopy. Moreover, 25-50 mg of the biopsy material was homogenized and the following enzyme activities were determined in 20,000 g supernatant: for cytochrome P450-dependent monooxygenase activity with 7-ethoxycoumarin O-deethylase (EOD) and with nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome c reductase and for conjugation activity with 1-naphthol glucuronyltransferase (NGT). The NGT and reductase activities were unchanged by the dietary alterations. However, the EOD activity was significantly depressed on semisynthetic diet and rose to control range on home diet (from 5.3 +/- 2.5 to 12.4 +/- 8.6 pmol/min X 10 mg wet wt). Male subjects had significantly higher EOD activities than female subjects on semisynthetic diet (6.6 +/- 2.3 vs. 3.2 +/- 0.9) as well as on home diet (16.3 +/- 9.0 vs. 6.4 +/- 3.0). Semisynthetic diet also reduced the jejunal villous height significantly when compared with home diet (408 +/- 49 vs. 373 +/- 44 micron). Therefore, on semisynthetic diet the toxicity of dietary xenobiotics that are inactivated by the intestinal mucosa may be increased.
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PMID:Effects of semisynthetic diets on xenobiotic metabolizing enzyme activity and morphology of small intestinal mucosa in humans. 642 5

Male mice were fed a diet containing less than 0.01 ppm selenium (Se-) for 6 months. A control group received the same diet containing 0.5 ppm selenium (Se+). In the livers of the Se- animals a drastic decrease in glutathione peroxidase (GSH-Px) activity was observed. It reached undetectable levels after 17 days of the Se- diet. At that time, GSH-transferase activity began to increase significantly, followed by changes in many other enzyme activities. After the 60th day, these enzyme modulations had reached a plateau with the following percentage changes compared to controls: GSH-transferases: 320% (1,2-dichloro-4-nitrobenzene), 218% (1-chloro-2,4-dinitrobenzene); glutathione reductase: 160%; ethoxycoumarin deethylase: 330%; cytochrome P-450-hydroperoxidase: 230%; heme oxygenase: 240%; UDP-glucuronyltransferase: 200%; GSH-thioltransferase: 64%; sulphotransferase: 62%; NADPH-cytochrome-P-450-reductase: 65%; flavin-containing mono-oxygenase: 57%. No significant changes were observed for GSH-transferase activity assayed with ethacrynic acid or for microsomal H2O2 formation and aniline hydroxylase activity. In single-pulse repletion experiments by injection of 250 micrograms selenium/kg body wt, different individual time constants for the recovery process of the enzymatic perturbations were observed. The half-times for the recovery ranged from 5.7 hr for the microsomal NADPH-cytochrome-P-450 reductase to over 29 hr for GSH-Px up to 44 hr for part of the GSH-transferase activity. 250 micrograms selenium/kg body wt were needed to restore 50% of GSH-Px activity in the long-term Se- mice compared to Se+ controls. All other enzymatic changes in the Se- mice needed a dose of 7 micrograms selenium/kg body wt for 50% restorage . The results demonstrate that processes other than those related to GSH-Px take place in a later phase of selenium deficiency in mouse liver with a chronologically common beginning. The different repletion and depletion kinetics as well as the different need of these processes for the trace element are discussed with respect to the existence of two separate selenium pools.
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PMID:Selenium and drug metabolism--II. Independence of glutathione peroxidase and reversibility of hepatic enzyme modulations in deficient mice. 642 18


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