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:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biotransformation or drug-metabolising enzymes have an important function in the detoxication of ingested toxic, carcinogenic, or tumour promoting compounds. Enzyme activity and isoenzyme composition of three biotransformation systems: glutathione S-transferase, uridine diphosphate-glucuronosyltransferase, and cytochrome P-450 were studied in normal small and large intestinal mucosa from three kidney donors. The activity of most drug-metabolising enzymes decreases slightly from proximal to distal small intestine, whereas in the mucosa of the large intestine a sharp fall in activity was observed. The isoenzyme composition for each of the three biotransformation systems changed from the small to the large intestine. Class Alpha glutathione S-transferases were not expressed in the colon, in contrast to the small intestine where both Alpha and Pi class isoenzymes are present. In addition, with monoclonal antibodies fewer protein bands for UDP-glucuronosyltransferases and cytochrome P-450 were detected in the colon. In the small intestine both isoforms P-450(4) and P-450(5) were present, whereas in the colon only reduced amounts of cytochrome P-450(4) could be visualised. For UDP-glucuronosyltransferase, 53 and 54 kDa proteins could be detected in the small intestine, but in the colon there was only weak staining of the 54 kDa band. In the normal human colon enzymes are less active and there are fewer isoenzymes present in the mucosa than in the small intestine. This implies a lower level of the detoxifying potential in the colon, which might be important in regard to the high rates of carcinogenesis in the colon.
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PMID:Biotransformation enzymes in human intestine: critical low levels in the colon? 190 9

The drug-metabolizing enzymes of olfactory and respiratory epithelium of cattle were determined. The data of nasal tissues were compared to those of bovine liver. Both oxidative and nonoxidative enzyme activities were investigated. Many compounds including testosterone were used as substrates for the P450-dependent monooxygenase activities. The results demonstrated that the P450 content and all the activities assayed including reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase were much higher in the olfactory than in the respiratory mucosa and for some activities (hexamethyl-phosphoramide and dimethylnitrosamine N-demethylase, aniline hydroxylase, and ethoxycoumarin O-deethylase) the values in the olfactory tissue were even markedly higher than those of liver. Also the activities of some nonoxidative enzymes such as glutathione S-transferase, uridine 5'-diphosphate (UDP)-glucuronyl-transferase, and epoxide hydrolase were higher in the olfactory than in the respiratory mucosa but lower than in liver. The results taken together suggest that the olfactory and respiratory epithelium of cattle, which contain in addition to a wide array of nonoxidative enzymes multiple forms of P450, can be useful and easily available tissues to study the biotransformation processes of odorants.
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PMID:Drug-metabolizing enzymes in liver, olfactory, and respiratory epithelium of cattle. 194 98

The induction of oxidation and conjugation enzymes, the scavenging of carcinogen electrophiles, and the inhibition of aflatoxin B1 (AFB1) activation were examined as possible mechanisms of anti-carcinogenesis by indole-3-carbinol (I3C). Liver microsomal 7-ethoxycoumarin O-deethylase and 7-ethoxyresorufin O-deethylase activities were not induced significantly in rainbow trout fed diets containing 500-2000 ppm I3C for 8 days compared to trout fed the control diet. Furthermore, no detectable changes in the specific contents of cytochrome P-450 isozymes LM2 and LM4b, as measured by Western-blotting and immunoquantitation, were found in liver microsomes following dietary I3C administration. Dietary I3C had no significant effect on liver microsomal uridine diphosphate-glucuronyl-transferase activity, measured using the substrates 1-naphthol and testosterone, or on cytosolic glutathione S-transferase activity, measured using the substrate styrene oxide. The ability of I3C or its acid reaction products (RXM; generated by the reaction of I3C with HCl) to act as scavengers for the direct alkylating agent AFB1-8,9-Cl2 was examined. Addition of I3C or RXM to in vitro incubations did not inhibit the covalent binding of AFB1-8,9-Cl2 to calf thymus DNA. Kinetic analyses of microsome-mediated binding of AFB1 to DNA in vitro indicated that RXM inhibited the metabolic activation of AFB1. RXM increased the apparent Km for the AFB1-DNA binding reaction without changing the associated Vmax; the apparent Km values at 0, 3.5, 35, and 350 microM RXM were 35, 38, 66, and 86 microM for trout liver microsomes. RXM also inhibited the activation of AFB1 by rat liver microsomes, but I3C was not an effective inhibitor against AFB1-DNA binding mediated by either rat or trout liver microsomes. The results of the present study indicate that inhibition of microsome-activated AFB1 binding to DNA by I3C products may be of significant importance in I3C inhibition of hepatocarcinogenesis in trout and other species. The inhibition of carcinogen activation by I3C is contrasted with the mechanism of anti-carcinogenesis by beta-naphthoflavone, which involves induction of xenobiotic metabolizing enzymes.
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PMID:Mechanisms of anti-carcinogenesis by indole-3-carbinol. Studies of enzyme induction, electrophile-scavenging, and inhibition of aflatoxin B1 activation. 210 94

A qualitative and quantitative assessment was made of the development of hepatic drug-metabolizing enzymes (DME) in dogs as part of a study of the ability of animal test species to metabolize drugs. The following DME variables were measured in this study: amount of cytochromes P-450 and b5; activity of the NADPH and NADH-dependent reductases associated with each of these cytochromes; activity of cytochrome P-450-mediated enzymes, including aniline and coumarin hydroxylases, aminopyrine N-demethylase, and 7-ethoxycoumarin O-deethylase; activity of a uridine diphosphoglucuronic acid glucuronyl transferase with 4-methylumbelliferone as substrate; and glutathione-S-transferase activities, with dinitrochlorobenzene and dichloronitrobenzene as substrates. Most enzyme components had achieved maximal amount or activity by the fifth to eighth week after birth; they tended to decrease after weaning, although the activity of dichloronitrobenzene-glutathione transferase in geriatric dogs (312 to 525 weeks old) was approximately twofold greater than that of 8-week-old pups. There were no gender-related differences in any of the enzyme amounts or activities determined. Individual variation was pronounced even in the homogeneous colony from which these dogs were obtained.
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PMID:Maturational development of drug-metabolizing enzymes in dogs. 212 81

In humans, data on biotransformation enzymes in the intestine, and to a lesser extent in the liver, are rather scarce. Much knowledge about these enzymes is, therefore, obtained from animal studies. We were able to examine both small intestinal and hepatic tissue from a kidney donor and performed a systematic study on enzyme contents and distribution in these organs. In the small intestine the longitudinal distribution of cytochrome P450, glutathione S-transferase, and bilirubin uridine 5'-diphosphate (UDP)-glucuronosyltransferase declined from duodenum to ileum. Activity of 4-nitrophenol- and 4-methylumbelliferone UDP-glucuronosyltransferase increased or remained constant, respectively. Total and specific activity of most enzymes was much higher in the liver, except for bilirubin UDP-glucuronosyltransferase and glutathione S-transferase, where the small intestine contained 28.6% and 7.4% of total hepatic activity, respectively. The relatively great amount of bilirubin UDP-glucuronosyltransferase activity in the small intestinal mucosa of this patient, who probably suffered from Gilbert's syndrome, could indicate that under pathological conditions intestinal metabolism may contribute significantly to the clearance of bilirubin. With a monoclonal antibody, UDP-glucuronosyltransferase isoforms were immunodetectable in microsomes. In the liver, two bands, one of 57 kilodaltons and one in between 53 and 54 kilodaltons, were seen. In the proximal small intestine two isoforms (53 and 54 kilodaltons) were detected. However, in the distal small intestine where bilirubin UDP-glucuronosyltransferase activity was low, only one isoform (54 kilodaltons) was seen. This may indicate that bilirubin UDP-glucuronosyltransferase activity is correlated with the 53-kilodalton isoform. The presence of multiple UDP-glucuronosyltransferase isoforms in humans, similar to that described before in the rat, is further established by this study.
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PMID:Glutathione S-transferase, cytochrome P450, and uridine 5'-diphosphate-glucuronosyltransferase in human small intestine and liver. 249 79

The pulmonary metabolism of xenobiotics was investigated by measuring the glutathione content and the activity of the aryl hydrocarbon hydroxylase, epoxide hydrolase, glutathione S-transferase, and uridine 5' -diphosphoglucuronosyl transferase enzymes in S-12 fractions of bronchial tree and peripheral lung parenchyma obtained at surgery from 21 patients. In parallel, the same preparations were used to assess either the activation of promutagens, i.e., benzo(a)pyrene, 2-aminofluorene, cyclophosphamide, and a cigarette smoke condensate, to metabolites reverting his- Salmonella typhymurium strains, or the decrease of direct-acting mutagens, i.e., sodium dichromate, 4-nitroquinoline N-oxide, epichlorohydrin, and ICR 191. As compared to bronchus preparations, parenchymal preparations contained considerably higher concentrations of reduced glutathione, had a significantly higher epoxide hydrolase activity, and, as assessed by means of a quantitative index, were more efficient in activating 2-aminofluorene and in reducing the mutagenicity of dichromate and 4-nitroquinoline N-oxide. These data may suggest that parenchymal lung tissue is more capable than bronchial tissue to detoxify reactive intermediates of xenobiotics, possibly explaining the greater susceptibility of bronchi to cigarette smoke-induced cancers.
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PMID:Carcinogen metabolism studies in human bronchial and lung parenchymal tissues. 250 89

Using male Fischer 344 rats classified as young (2-4 months), middle aged (12-14 months), and old (22-25 months), the activities of several Phase I and Phase II biotransformation pathways in the large intestine were investigated, including benzo[a]pyrene hydroxylase (BPOH), alcohol dehydrogenase (ADH), glutathione S-transferase (GST), glutathione peroxidase (GSH-PX), beta-glucuronidase (BG), and microsomal and nuclear glucuronyltransferase (UDPGT). Levels of oxidized (GSSG) and reduced (GSH) glutathione and uridine 5'-diphosphoglucuronic acid (UDPGA) were also measured. BPOH increased 33% in old rats, while ADH and BG activity remained unchanged with age. Nuclear UDPGT remained unchanged with age, whereas form I of GSH-PX declined slightly in old rats. GST, microsomal UDPGT, and form II of GSH-PX declined by 38, 37 and 44%, respectively, in old rats. The decrease in GST and microsomal UDPGT was also significant in middle aged rats. Levels of colonic GSH, GSSG and UDPGA were found to be unchanged with age. These in vitro data suggest the possibility that if reactive intermediates are generated to the same extent in old rats as in young rats, decreased detoxification mechanisms in the old rat may increase susceptibility of the colon to actions of chemical carcinogens.
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PMID:Changes in phase I and phase II biotransformation with age in male Fischer 344 rat colon: relationship to colon carcinogenesis. 311 59

A major concern of contemporary medicine is the adverse effects resulting from the use of prescribed and over-the-counter pharmacologic agents. In many cases more than one drug is taken at the same time, which increases the risk of overloading the detoxification mechanisms. If the individual has poor nutritional status, the system becomes even more inefficient. The liver contains the most important of these detoxification systems: the cytochrome P-450-dependent mixed function oxidase (MFO) and several conjugation enzymes, e.g., sulfotransferase, glucuronyl transferase, and glutathione transferase, which convert lipophilic compounds to more water-soluble products to enhance their excretion. The balance of these reactions determines the rate of metabolism and clearance of xenobiotic agents, and regulates in part the degree of intracellular damage. Nutritional factors, including proteins, carbohydrates, fats, vitamins, and minerals, affect the efficiency of these reactions. Changes in intracellular metabolism can alter not only the enzyme levels but also the availability of their cofactors, e.g., NADPH, UDPGA (uridine diphosphate glucuronic acid), PAPS (3'-phosphoadenosine-5'-phosphosulfate), and GSH. Diets restricted in calories, protein, or essential fatty acids, as well as those having low quality protein or high sugar content, can affect the component enzymes, cytochrome P-450 and the cytochrome P-450 reductase, and the MFO activity toward a variety of drugs. In addition, deficiencies of specific vitamins (riboflavin, ascorbic acid, and vitamins A and E) and minerals (iron, copper, zinc, and magnesium) affect the components and activities of the system in unique ways. Insight into the regulation of the hepatic detoxification mechanism can be gained by using nutrient variables to perturb the system.
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PMID:Nutritional parameters that alter hepatic drug metabolism, conjugation, and toxicity. 351 Sep 12

Adult male rats were sorted into control and infected groups, the latter receiving an oral dose of 20 metacercariae of Fasciola hepatica. In Weeks 3 and 6 after infection, some rats received phenobarbital or 3-methylcholanthrene which induced drug metabolizing enzymes. The parasitic pathology was ascertained by clinical observation of the rats and at autopsy. Hepatic microsomal cytochrome P-450 content was significantly decreased in infected rats compared to untreated phenobarbital treated groups. In all infected rats, the simultaneous increase in cytosolic calcium and decrease in cytosolic glutathione corresponded to oxidative cell injury occurring in the course of fascioliasis. Both arylamine acetyltransferase (EC 2.3.1.5.) and glutathione transferase (EC 2.5.1.18) activities were decreased in all newly infected and 6 week infected groups. Fascioliasis did not alter the substrate related uridine diphosphate glucuronosyltransferase activities (EC 2.4.1.17) of any rat group.
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PMID:Fasciola hepatica: liver enzymes in rats and interaction with chemical inducers. 356 74

The metabolism of (3H)-benzo(a)pyrene and the activities of enzymes involved in its metabolism were studied in rat lung and liver in vitamin A deficiency. Deficiency of vitamin A resulted a significant decrease in the overall metabolism of benzo(a)pyrene in the liver in vitro, whereas no significant difference was evident in the lung. The ethyl acetate-soluble metabolites of benzo(a)pyrene formed by lung and liver preparations were unaltered qualitatively by vitamin A deficiency. However, quantitative analysis revealed that vitamin A deficiency decreased the yield of dihydrodiols, quinones and phenols in liver, and dihydrodiols in lung. The hepatic cytochrome P-450 content, arylhydrocarbon hydroxylase and uridine diphosphate-glucuronosyl transferase activities were reduced, whereas glutathione S-transferase activity was increased in the vitamin A deficient animals. Contrary to this, pulmonary cytochrome P-450 content was above the control values (p less than 0.01) and no alteration in pulmonary arylhydrocarbon hydroxylase activity was observed in vitamin A deficient rats. Uridine diphosphate-glucuronosyltransferase and glutathione S-transferase activities were impaired in lung by inducing vitamin A deficiency. However, no significant difference was evident in the overall metabolism of benzo(a)pyrene by lung supernatants from the two groups.
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PMID:Effect of vitamin A deficiency on pulmonary and hepatic in vitro metabolism of benzo(a)pyrene in rat. 393 30


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