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)

In an attempt to better understand breast tumors sensitivity or resistance to anticancer drugs, the main drug-metabolizing enzyme systems were evaluated in both breast tumors and their corresponding peritumoral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione S-transferases (GST-alpha, -mu, and -pi); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: GST; total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the absence of all probed cytochromes P-450 in both tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) higher in tumors (mean +/- SD, 399 +/- 362 nmol/min/mg) than in corresponding peritumoral tissues (86 +/- 67). The GST isoenzymes GST-mu and GST-pi (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-mu and GST-pi levels were significantly correlated with GST activity. GST-alpha was not detected in either tumoral or peritumoral tissues. Glutathione levels in tumors (22 +/- 23 nmol/mg protein) were not statistically different from peritumoral tissues (11 +/- 12). Epoxide hydrolase was expressed at similar levels in tumors and peritumoral tissues. The glucuronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tumors (0.1 +/- 0.2 nmol/h/mg) than in peritumoral tissues (0.5 +/- 1), whereas the opposite was observed for the hydrolytic enzyme beta-glucuronidase, which was 6-fold higher in tumors (736 +/- 1392 nmol/h/mg) compared to peritumoral tissues (125 +/- 75). No difference was noted between tumoral and peritumoral tissues for sulfotransferase (1 +/- 2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tissues (14 +/- 15 nmol/h/mg) than in peritumoral tissues (6 +/- 2). In conclusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-mu, GST-pi, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and beta-glucuronidase). These noteworthy differences between tumoral and peritumoral tissues with regard to their main drug-metabolizing enzymes could play a role in the relative drug sensitivity or insensitivity of human breast cancer tissues to chemotherapeutic agents and could be potential targets for chemotherapeutic interventions.
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PMID:Main drug-metabolizing enzyme systems in human breast tumors and peritumoral tissues. 833 60

Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
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PMID:Metabolic polymorphisms. 836 90

The effect of a nitrogen heterocycle constituent on the ability of arylmethanes to induce phase I and phase II drug-metabolizing enzymes has been examined. Rats were treated with tetra-, tri-, di- or monoarylmethane compounds daily for 3 days at a dose of 75 mg/kg. Induction of UDP-glucuronosyltransferase (morphine) activity was seen with twelve of the eighteen compounds investigated, and for three compounds it occurred independent of any induction of cytochrome P450. Induction of glutathione S-transferase activity was seen with ten of the compounds and was generally paralleled by changes in overall cytochrome P450 concentration and in both pentoxyresorufin and erythromycin dealkylase activities. Major induction of ethoxyresorufin deethylase activity was only apparent with two diarylmethanes that contained a 1-substituted imidazole moiety. UDP-glucuronosyltransferase (1-naphthol) activity was coinduced by these two compounds. A third compound, diphenyl-4-pyridylmethane, induced UDP-glucuronosyltransferase (1-naphthol) activity without increasing ethoxyresorufin deethylase activity. Cytosolic sulfotransferase activity was not induced by the administration of any compound in this study. Among arylmethane derivatives, the presence of two aryl groups appeared to be a minimum requirement for induction of drug-metabolizing enzymes. If one of the aryl groups was not a heterocycle, or if the nitrogen atom of the heterocycle was sterically hindered, major induction of cytochrome P450 did not occur. With triarylmethanes, induction was independent of whether the heterocycle was imidazole, pyridine or pyrimidine.
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PMID:Induction of rat liver drug-metabolizing enzymes by heterocycle-containing mono-, di-, tri- and tetra-arylmethanes. 836 42

To better understand the importance of drug-metabolizing enzymes in carcinogenesis and anticancer drug sensitivity of human non-small cell lung cancer, we studied the main drug-metabolizing enzyme systems in both lung tumors and their corresponding nontumoral lung tissues in 12 patients. The following enzymes were assayed by Western blot analysis: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); epoxide hydrolase; and glutathione S-transferase isoenzymes (GST-alpha, -mu, and -pi). The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: glutathione S-transferase (GST); total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the presence of cytochrome P-450 1A1/1A2 in both tumoral and nontumoral tissues. P-450 1A1/1A2 levels were 3-fold lower in tumors compared to corresponding nontumoral tissues (P < 0.05). None of the other probed cytochromes P-450 were detected in either tumoral or nontumoral lung tissues. For the glutathione system, no significant difference between tumoral and nontumoral tissues was observed (GST activity, glutathione content, GST-alpha, -mu, and -pi). A positive linear correlation was observed between GST activity and GST-alpha or GST-pi. No significant difference was observed for the glucuronide and the sulfate pathways and their corresponding hydrolytic enzymes. Epoxide hydrolase was significantly decreased in tumors compared to nontumoral lung tissues (P < 0.05). In conclusion, these results showed differences between non-small cell lung tumors and nontumoral tissues for cytochrome P-450 1A1/1A2 and epoxide hydrolase. These differences between tumors and peritumoral tissues with regard to these drug-metabolizing enzymes could reflect differences occurring after malignant transformation and may play a role in drug sensitivity to anticancer drugs.
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PMID:Main drug- and carcinogen-metabolizing enzyme systems in human non-small cell lung cancer and peritumoral tissues. 840 35

1. Among nitrogen heterocycles based on the planar phenanthrene structure are three (1,7- and 4,7-phenanthroline and phenanthridine) which selectively increase rat hepatic phase II drug metabolizing enzyme activities without increasing cytochrome P450 concentration. Of six monooxygenase activities investigated, only ethoxyresorufin dealkylase was raised but this was only minor. 2. The detergent-activated UDP-glucuronosyltransferase activities towards morphine, 4-nitrophenol, and 1-naphthol were increased up to five-, three- and two-fold of control respectively. Microsomal epoxide hydrolase activity towards cis-stilbene oxide was increased up to three-fold and cytosolic glutathione S-transferase activity towards 1-chloro-2, 4-dinitrobenzene reached twice the control value. 3. Cytosolic 4-nitrophenol sulphotransferase activity was not increased by any compound and like some monooxygenase reactions, was decreased by 4,7- and 1,7-phenanthrolines. 4. 1,10-Phenanthroline and two compounds which lack a heterocyclic nitrogen atom, (phenanthrene and 9-phenanthrol), failed to elicit any induction of enzyme activities. 5. Changes in microsomal epoxide hydrolase activity showed high correlation (r = 0.97) with changes in UDP-glucuronosyltransferase (4-nitrophenol) activity.
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PMID:Selective induction of rat liver phase II enzymes by N-heterocycle analogues of phenanthrene: a response exhibiting high correlation between UDP-glucuronosyltransferase and microsomal epoxide hydrolase activities. 849 89

The olfactory epithelium is exposed to a variety of xenobiotic chemicals, including odorants and airborne toxic compounds. Recently, two novel, highly abundant, olfactory-specific biotransformation enzymes have been identified: cytochrome P-450olf1 and olfactory UDP-glucuronosyltransferase (UGT(olf)). The latter is a phase II biotransformation enzyme which catalyses the glucuronidation of alcohols, thiols, amines and carboxylic acids. Such covalent modification, which markedly affects lipid solubility and agonist potency, may be particularly important in the rapid termination of odorant signals. We report here the identification and characterization of a second olfactory phase II biotransformation enzyme, a glutathione S-transferase (GST). The olfactory epithelial cytosol shows the highest GST activity among the extrahepatic tissues examined. Significantly, olfactory epithelium had an activity 4-7 times higher than in other airway tissues, suggesting a role for this enzyme in chemoreception. The olfactory GST has been affinity-purified to homogeneity, and shown by h.p.l.c. and N-terminal amino acid sequencing to constitute mainly the Yb1 and Yb2 subunits, different from most other tissues that have mixtures of more enzyme classes. The identity of the olfactory enzymes was confirmed by PCR cloning and restriction enzyme analysis. Most importantly, the olfactory GSTs were found to catalyse glutathione conjugation of several odorant classes, including many unsaturated aldehydes and ketones, as well as epoxides. Together with UGT(olf), olfactory GST provides the necessary broad coverage of covalent modification capacity, which may be crucial for the acuity of the olfactory process.
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PMID:Glutathione S-transferases in rat olfactory epithelium: purification, molecular properties and odorant biotransformation. 850 73

We examined the role of dietary lipids in regulating the activities and amounts of epoxide hydrolase, UDP-glucuronosyltransferase and glutathione S-transferase in rat liver. Male Wistar rats were fed a fat-free (FF) diet or isocaloric control diet containing 5% corn oil (CO) or 5% fish oil (FO) for 3 weeks. The activities of these enzymes were approx. 2-fold higher in rats fed the FO diet vs. the FF diet. Intermediate levels of enzyme activity were found in rats fed the CO diet. Diet-induced differences in enzyme levels were shown by immunoblotting. The highest levels of epoxide hydrolase, UDP-glucuronosyltransferase and glutathione S-transferase were detected in rats fed the FO diet. The lowest levels of these enzymes were found in rats fed the FF diet. Intermediate levels of enzyme were found in rats fed the CO diet. Thus, diet-induced differences in enzyme activities were paralleled by changes in enzyme levels. Fatty acid analysis of microsomal lipids showed that the FF diet was associated with decreased levels of n-6 fatty acids vs. the CO diet. The FO diet resulted in increased levels of n-3 fatty acids vs. the other diets.
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PMID:Dietary lipids coinduce xenobiotic metabolizing enzymes in rat liver. 850 42

The effect of genetic obesity and phenobarbital treatment on hepatic conjugation pathways was evaluated in the obese Zucker rat. Acetaminophen pharmacokinetic parameters were examined in vivo after a 30-mg/kg acetaminophen intravenous bolus dose in the presence and absence of phenobarbital treatment. Glucuronidation and glutathione conjugation pathways were studied in vitro in obese and lean Zucker rats after phenobarbital treatment. Obese Zucker rats demonstrated a higher glucuronidation capacity as evidenced by a higher formation clearance of acetaminophen glucuronide and greater UDP-glucuronosyltransferase (UDPGT) activity toward acetaminophen and p-nitrophenol compared with lean controls. Sulfate and glutathione conjugation pathways were not affected by genetic obesity. Obese Zucker rats possessed a higher total hepatic glutathione content due to greater liver weight. Phenobarbital treatment enhanced glucuronidation of acetaminophen and structurally related compounds (i.e., p-nitrophenol) similarly in both phenotypes, but the treatment failed to induce morphine UDPGT in the obese Zucker rat. No effect of phenobarbital was observed on sulfate conjugation, gamma-glutamyl cysteine synthetase activity or hepatic glutathione content in obese or lean Zucker rats. Similar increases in glutathione transferase activities were observed in animals of both phenotypes after phenobarbital treatment. This study demonstrates that glucuronidation is enhanced in genetically obese rats, whereas phenobarbital causes normal induction of several enzymes of the glucuronidation and glutathione conjugation pathways in the obese Zucker rat. However, morphine UDPGT was not induced by phenobarbital, suggesting that obese Zucker rats may possess a defect in the induction of this enzyme similar to that already described for the CYP2B gene in this strain.
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PMID:Effect of genetic obesity and phenobarbital treatment on the hepatic conjugation pathways. 851 12

Non-Hodgkin's lymphomas (NHL) are one of the most chemosensitive human malignancies. Complete response (CR) is often achieved, but many patients relapse and a second CR is difficult to obtain because of the development of chemoresistance. In an attempt to better understand the biology and the chemosensitivity of these lymphoid tumors, we assessed the main drug-metabolizing enzyme systems in normal lymphocytes, chemosensitive NHL and chemoresistant NHL. Cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase and glutathione S-transferases (GST-alpha, -mu, -pi) were assayed by immunoblotting. UDP-glucuronosyltransferase, beta-glucuronidase, sulfotransferase, sulfatase, GST activity, and glutathione (GSH) content, were determined by spectral assays. Results showed the absence of all probed cytochromes P-450 in normal lymphocytes and NHL cells tested. GST activity was significantly lower in chemoresistant NHL compared to normal lymphocytes. GST-alpha was not detected in either normal lymphocytes or NHL cells. GST-pi was the predominant isoenzyme, and GST-mu was not detected in chemosensitive NHL. GSH content was significantly lower in chemoresistant NHL compared to other lymphoid tissues tested. The conjugating enzymes UDP-glucuronosyltransferase and sulfatase were similar in either chemoresistant NHL compared to chemosensitive NHL. The activity of the hydrolytic enzyme beta-glucuronidase was lower in chemoresistant compared to chemosensitive NHL, whereas sulfatase was higher in sensitive NHL compared to normal lymphocytes. Epoxide hydrolase was not detected in either normal or NHL cells tested. In conclusion, these studies did not show any cytochrome P-450 in human lymphoid cells tested, but pointed out noteworthy differences for other enzyme systems tested.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Main drug-metabolizing enzyme systems in human non-Hodgkin's lymphomas sensitive or resistant to chemotherapy. 853 97

The metabolism of probe substrates of phase I and phase II enzymes in vitro were compared in hepatic subcellular fractions from humans, cynomolgus monkeys, rhesus monkeys, and beagle dogs. These studies were undertaken to compare the suitability of these species as models of metabolism in drug development. Eight cytochrome P450-dependent activities were measured in microsomal incubations: ethoxyresorufin O-deethylase, coumarin 7-hydroxylase, tolbutamide 4-hydroxylase, S-mephenytoin 4'-hydroxylase, bufuralol 1'-hydroxylase, N-nitrosodimethylamine N-demethylase, midazolam 1'-hydroxylase, and erythromycin N-demethylase. Seven phase II activities were determined in the appropriate subcellular fractions:acetaminophen UDP-glucurono-syltransferase, acetaminophen sulfotransferase, 17 alpha-ethinylestradiol UDP-glucuronosyltransferase, 17 alpha-ethinylestradiol sulfotransferase, 6-mercaptopurine methylase, dichloronitrobenzene (DCNB) glutathione S-transferase, and isoniazid N-acetylase. Hepatic subcellular fractions from cynomolgus and rhesus monkeys showed significantly higher activities than those from humans for ethoxyresorufin O-deethylase, bufuralol 1'-hydroxylase, midazolam 1'-hydroxylase, erythromycin N-demethylase, acetaminophen UDP-glucuronosyltransferase, acetaminophen sulfotransferase, and tolbutamide 4-hydroxylase. Cynomolgus monkey had higher activity than humans and rhesus monkeys for S-mephenytoin 4'-hydroxylase erythromycin N-demethylase. Rhesus monkey and human cytosol displayed an apparent genetic polymorphism in the N-acetylation of isoniazid, whereas cynomolgus monkey cytosol did not. All other monkey activities were not significantly different than human. Dog subcellular fractions showed higher activity than humans for midazolam 1'-hydroxylase, erythromycin N-demethylase, acetaminophen UDP-glucuronosyltransferase, acetaminophen sulfotransferase, 17 alpha-ethinylestradiol sulfotransferase, and DCNB glutathione S-transferase. Furthermore, dog samples had significantly lower activity for coumarin 7-hydroxylase and 6-mercaptopurine methylase, and no detectable activity for tolbutamide 4-hydroxylase or isoniazid N-acetylase. All other activities were not significantly different from human. These results reveal minor differences between the cynomolgus and rhesus monkey in drug metabolism capacities in vitro, but both species are generally more metabolically active than humans in both phase I and phase II metabolism, whereas dogs had more diverse deviations from humans.
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PMID:Comparisons of phase I and phase II in vitro hepatic enzyme activities of human, dog, rhesus monkey, and cynomolgus monkey. 859 24


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