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)

The cortex and medulla were isolated from kidneys whose donors (5 men and 1 woman, aged between 44 and 68 years) were undergoing nephrectomy to remove a tumor. Kidneys with normal architecture for at least two thirds of the organ were included in the study. Tissue specimens used in our experiments were free from pathological changes. The activities of the following enzymes of phase I NADPH cytochrome c reductase, aminopyrine N-demethylase, ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase, microsomal and cytosolic epoxide hydrolases, glutathione reductase and glutathione peroxidase, and those of the following enzymes of phase II glutathione transferase, glucuronyl transferase, sulphotransferase, acetyltransferase, thiomethyltransferase, thiopurinemethyltransferase, thioltransferase and glyoxalase were measured. The activity in renal cortex was significantly higher than in medulla for NADPH cytochrome c reductase, cytosolic epoxide hydrolase, glutathione reductase and glutathione peroxidase (phase I enzymes), and glutathione transferase, acetyltransferase, thiomethyltransferase, thiopurinemethyltransferase, thioltransferase and glyoxalase (phase II enzymes). The other enzymes had similar activity in cortex and medulla. The distribution pattern of drug-metabolizing enzymes in the human kidney cannot be considered as a single pattern because of the observed enzyme-dependent differences between cortex and medulla.
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PMID:Profile of drug-metabolizing enzymes in the cortex and medulla of the human kidney. 261 33

Six patients (4 women and 2 men, age between 60 and 90 years), subjected to right hemicolectomy, were gut donors. The mucosa was isolated from the last portion of the ileum and the first portion of the colon. Tissue specimens were free from pathological changes. The activities of the enzymes of phase I (NADPH cytochrome c reductase, ethoxycoumarin O-deethylase, aminopyrine N-demethylase, microsomal epoxide hydrolase, cytosolic epoxide hydrolase, glutathione reductase and glutathione peroxidase) and the enzymes of phase II (glutathionetransferase, glucuronyltransferase, acetyltransferase, thioltransferase, sulphotransferase and glyoxalase) were measured in the microsomal or cytosolic fractions obtained from ileum and colon mucosa. The activity in the ileum was higher than in the colon for NADPH cytochrome c reductase (p less than 0.05) and cytosolic epoxide hydrolase (p less than 0.001) (phase I enzymes), and glutathionetransferase (p less than 0.02), sulphotransferase (p less than 0.05) and glyoxalase (p less than 0.02) (phase II enzymes). The other enzymes had similar activities in two mucosa. The distribution pattern of drug metabolizing enzymes cannot be considered as a single pattern in human ileum and colon because of the observed enzyme-dependent differences.
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PMID:Profile of drug-metabolizing enzymes in human ileum and colon. 272 51

Glucuronidation of 4-nitrophenol, nopol (a monoterpenoid alcohol) and bilirubin, which in the rat, are catalyzed by three different enzymes, has been examined in liver biopsies from patients with various liver diseases, in particular cholestasis. These different activities were not correlated, which strongly suggests that at least three independently regulated forms of UDP-glucuronosyltransferases were present in the microsomes. Non ionic detergents (Triton X100, Emulgen 911) and deoxycholate produced similar activation (more than 2-fold) of the glucuronidation of 4-nitrophenol. Amphipathic substances, such as CHAPS (3-[3-cholamidopropyl-dimethylammonio]-1-propane sulfonate), and lysophosphatidylcholines maximally increased this UDP-glucuronosyltransferase activity, the most potent being oleoyl lysophosphatidylcholine (4-fold increase). Discriminant analysis of the data revealed no correlation between the three different UDP-glucuronosyltransferase activities and the age or sex of the patients. A good correlation was found on multidimensional analysis between form 1 of the enzyme (4-nitrophenol glucuronidation) and, in decreasing order of magnitude, epoxide hydrolase (measured with benzo(a)pyrene-4,5-oxide as substrate), cytochrome P-450, 7-ethoxycoumarin deethylase, aspartate aminotransferase and gamma-glutamyltransferase (r = 0.89); and between Form 3 of the enzyme (bilirubin glucuronidation) and NADPH cytochrome c reductase, alkaline phosphatase, (r = 0.81). These relationships may reflect the differential variation in enzymatic activities in various hepato-biliary diseases.
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PMID:Properties of human hepatic UDP-glucuronosyltransferases. Relationship to other inducible enzymes in patients with cholestasis. 288 32

Human lung cancer cell lines in culture were investigated for the expression of monooxygenase and other xenobiotic-metabolizing enzyme activities. Two bronchiolo-alveolar carcinoma derived cell lines (NCI-H322 and NCI-H358) and two small-cell carcinoma derived cell lines (NCI-H128 and NCI-H69) were used. Previous work has shown that NCI-H322 has ultrastructural features of Clara cells while NCI-H358 shows characteristics of alveolar type II cells [Schuller et al., Proc. Am. Ass. Cancer Res. 26, 27 (1985)]. NCI-H128 and NCI-H69 show very poor differentiation of cytoplasmic organelles. Cytochrome P-450 levels were spectroscopically detectable only in NCI-H322. Both NCI-H322 and NCI-H358, but not NCI-H69 and NCI-H128, exhibited aryl hydrocarbon hydroxylase (using benzo[a] pyrene as substrate) and ethoxycoumarin O-deethylase activities. These activities were highly inducible following pretreatment with the polycyclic aromatic hydrocarbons (PAH) beta-naphthoflavone or benzo[a] anthracene. The PAH produced a 2-fold increase in spectroscopically detectable cytochrome P-450 levels in NCI-H322. Following induction, cytochrome P-450 was also spectroscopically detectable in NCI-H358. No aldrin epoxidase activity was present in either untreated or pretreated cell lines. Pretreatment with phenobarbitone or dexamethasone did not induce the aryl hydrocarbon hydroxylase activity in either NCI-H322 or NCI-H358. The ethoxycoumarin O-deethylase activity in beta-naphthoflavone-pretreated NCI-H322 and NCI-H358 was inhibited in a concentration-dependent manner by ellipticine, alpha-naphthoflavone, cimetidine or metyrapone. Untreated NCI-H322 and NCI-H358 also contained cytochrome b5, NADPH cytochrome c reductase and epoxide hydrolase activities. None of these enzyme activities measured was detectable in the untreated or pretreated small-cell derived cancer cell lines (NCI-H128 and NCI-H69). These data show that the two bronchiolo-alveolar carcinoma derived cell lines (NCI-H322 and NCI-H358) exhibit cytochrome P-448-dependent monooxygenase activity and may thus prove useful to study the processes of xenobiotic activation in human lung.
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PMID:Xenobiotic-metabolizing enzyme activity in human non-small-cell derived lung cancer cell lines. 300 5

Specific polyclonal antibodies were used to investigate the distribution of two cytochrome P-450 isozymes (5 and 8), NADPH cytochrome c reductase, and epoxide hydrolase in adult human hepatocytes cultured alone or co-cultured with rat liver epithelial cells. The enzymes were localized by the indirect immunoperoxidase technique following fixation with a paraformaldehyde-glutaraldehyde mixture and membrane permeabilization with saponin. The pattern of distribution of the four enzymes after 24 hr in culture was similar to that found in vivo. Virtually all the hepatocytes exhibited nearly homogeneous positive staining for cytochrome P-450-8, whereas only 60-80% were positive for cytochrome P-450-5. Nearly homogeneous staining was also observed in all hepatocytes for NADPH cytochrome c reductase and epoxide hydrolase. During the first 12 days in pure culture, the intensity of staining, as well as the number of positively stained cells, decreased slightly except for epoxide hydrolase, which did not show any obvious change. In contrast, even after 15 days in co-culture the extent of staining for all the enzymes decreased less than in pure culture. These results indicate that adult human hepatocytes continue to express specific drug-metabolizing enzymes for several days in culture and provide further evidence that those cells are more stable than rodent hepatocytes in primary culture.
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PMID:Immunocytochemical evidence for the maintenance of cytochrome P-450 isozymes, NADPH cytochrome C reductase, and epoxide hydrolase in pure and mixed primary cultures of adult human hepatocytes. 308 26

In 8-day-old rat pups, pretreatment with a single injection of L-triiodothyronine or L-thyroxine decreased hepatic cytochrome P-450 content, aminopyrine N-demethylase activity and epoxide hydrolase activity but increased hepatic microsomal cytochrome c reductase, 7-ethoxyresorufin O-deethylase and heme oxygenase activities without significantly altering UDP-glucuronosyltransferase activity (towards o-aminophenol) or the microsomal yield. In adult rats of either sex such single injections of L-triiodothyronine failed to significantly alter these enzyme activities. However, multiple injections evoked changes similar to those observed in the pups, in all these enzyme activities, except that 7-ethoxyresorufin O-deethylase activity was slightly decreased rather than increased. These findings demonstrate that: (1) The hepatic monooxygenase system in the rat pup is more responsive to thyroid hormones than that in adult. (2) Thyroid hormones can decrease rat liver cytochrome P-450 content and its dependent monooxygenase activity independently of sexual maturity. (3) Thyroid hormones also decrease hepatic epoxide hydrolase activity in both pups and adults. Thus, hyperthyroidism could render the rat pup more susceptible to hepatotoxicity from electrophilic epoxides which utilize microsomal epoxide hydrolase as the major detoxication pathway.
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PMID:Thyroid hormone-induced changes in the hepatic monooxygenase system, heme oxygenase activity and epoxide hydrolase activity in adult male, female and immature rats. 680 67

Male 3-month-old Wistar rats dosed i.p. with 200 mg/kg of nitromethane or -ethane showed increased acid proteinase activity in the brain 4 h after the injection. The change was accompanied by a marginal increase in the cerebral glutathione concentration. Nitroethane caused enhanced epoxide hydrolase and UDP-glucuronosyltransferase activity in the hepatic microsomal fraction up to 48 h while 7-ethoxycoumarin o-deethylase decreased. These biochemical changes were accompanied by proliferation of smooth endoplasmic reticulum and degranulation and disorganization of the rough endoplasmic reticulum of the nitroethane-exposed liver cells. The hepatic effects of nitromethane were restricted to decreased cytochrome c reductase activity with proliferation of smooth endoplasmic reticulum. The results point at limited peroxidative damage possibly involving reduction of the nitrogroup.
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PMID:Comparison of acute toxic effects of intraperitoneally injected nitromethane and nitroethane in rats. 681 33

The influence of dietary cholesterol on drug metabolism was studied by feeding rats either a cholesterol-free or a high (2%) cholesterol diet for 4 weeks from weanling onward and giving phenobarbitone (Pb) and/or carbon tetrachloride (CCl4) thereafter. Pb was given in drinking water for 7 days at a dosage of 100 mg/kg and CCl4, at a dosage of 1.5 mg/kg SC 6 days before assays of drug-metabolizing enzymes. The cytochrome P-450 concentration was 2-fold in rats fed the 2% cholesterol diet in comparison with those fed the cholesterol-free diet. Only a weak induction by Pb was found in the cholesterol-free group. Only slight differences due to the cholesterol diets or due to the administration of xenobiotics were found in the NADPH cytochrome c reductase activity. The PPO hydroxylase activity was 2-fold in the livers of rats fed the 2% cholesterol diet in comparison with those fed the cholesterol-free diet. In the ethoxyresorufin deethylase activity, differences between diets were present first after the administration of xenobiotics. No change in the hepatic aryl hydrocarbon hydroxylase activity was found due to changes in the cholesterol content of the diets. The ethoxycoumarin O-deethylase activity was 2-fold in the livers of rats fed 2% cholesterol diet from those fed the cholesterol-free diet. The inducibility of ethoxycoumarin O-deethylase was equal, regardless of which diet was used. The hepatic epoxide hydrolase activity of rats fed 2% cholesterol was 3-fold in comparison with the cholesterol-free group. The inducibility by Pb was higher in the livers of the cholesterol-free (3.3-fold) than 2% cholesterol-fed rats (2.4-fold). The hepatic UDP-glucuronosyl-transferase activity was 1.5-fold in 2% cholesterol-fed rats in comparison with rats fed the cholesterol-free diet. The inducibility by CCL4 was found only in rats fed the cholesterol-free diet. The results suggest that dietary cholesterol modifies the enzyme activities in the liver and modifies their response to enzyme inducers.
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PMID:Dietary cholesterol-induced changes of xenobiotic metabolism in liver. II. Effects of phenobarbitone and carbon tetrachloride on activities of drug-metabolizing enzymes. 682 90

1. The effects of feeding allyl sulphides to rat (2000 ppm of the diet for 15 days) were investigated on various microsomal hepatic drug-metabolizing enzymes by their immunochemical detection and catalytic activity. 2. Allyl sulphides provoked a temporary dietary restriction, which enhanced the microsomal level of P450 and the activities of NADH-cytochrome c reductase and p-hydroxybiphenyl UDP-glucuronyltransferase (UDPGT 2), and lowered the activities of p-nitrophenol hydroxylase (PNPH), N-nitrosodimethylamine demethylase (NDMAD), laurate omega-hydroxylase (LAH) and glutathione S-transferase (GST). Therefore, pair-fed animals were used as a more relevant control for the dietary effects of allyl sulphides. 3. Diallyl sulphide (DAS) as well as diallyl disulphide (DADS) produced an enhancement of the microsomal level of P4501A2, 2B1/2 and 3A1/2, and epoxide hydrolase (EH) proteins, with an increase in the enzymatic activities they catalyse: ethoxyresorufin O-deethylase (EROD), aryl hydrocarbon hydroxylase (AHH), methoxyresorufin O-demethylase (MROD), ethoxycoumarin O-deethylase (ECOD), pentoxyresorufin O-depentylase (PROD), benzoxyresorufin O-debenzylase (BROD) and EH. Although P4502E1 proteins were lowered on treatment, NDMAD activity was not modified, and PNPH activity was even enhanced by allyl sulphides. Only DAS treatment raised erythromycin N-demethylase (ERDM) activity. 4. Both DAS and DADS increased the activity of GST and p-nitrophenol UDP-glucuronyltransferase (UDPGT 1), whereas UDPGT 2 activity was enhanced only by DAS.
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PMID:Modification of hepatic drug-metabolizing enzymes in rat fed naturally occurring allyl sulphides. 801 91

Formation of free radicals and other reactive molecules is responsible for the adverse effects produced by a number of hepatotoxic compounds. cDNA microarray technology was used to compare transcriptional profiles elicited by training and testing sets of 15 oxidant stressors/reactive metabolite treatments to those produced by approximately 85 other paradigm compounds (mostly hepatotoxicants) to determine a shared signature profile for oxidant stress-associated hepatotoxicity. Initially, 100 genes were chosen that responded significantly different to oxidant stressors/reactive metabolites (OS/RM) compared to other samples in the database, then a 25-gene subset was selected by multivariate analysis. Many of the selected genes (e.g., aflatoxin aldehyde reductase, diaphorase, epoxide hydrolase, heme oxgenase and several glutathione transferases) are well-characterized oxidant stress/Nrf-2-responsive genes. Less than 10 other compounds co-cluster with our training and testing set compounds and these are known to generate OS/RMs as part of their mechanisms of toxicity. Using OS/RM signature gene sets, compounds previously associated with macrophage activation formed a distinct cluster separate from OS/RM and other compounds. A 69-gene set was chosen to maximally separate compounds in control, macrophage activator, peroxisome proliferator and OS/RM classes. The ease with which these 'oxidative stressor' classes can be separated indicates a role for microarray technology in early prediction and classification of hepatotoxicants. The ability to rapidly screen the oxidant stress potential of compounds may aid in avoidance of some idiosyncratic drug reactions as well as overtly toxic compounds.
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PMID:A gene expression signature for oxidant stress/reactive metabolites in rat liver. 1549 15


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