Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats and mice were exposed to the fumes of oxidative thermal degradation of polystyrene (350 degrees C). A decrease in the reduced glutathione (GSH) in both liver and lung was detected immediately after both the acute (mice, 3 h) and subacute (rats, 3 weeks) exposures were stopped. Later on an elevation in the amount of GSH due to the increased synthesis (rebound effect) could be seen. Cytochrome P-450 content in mouse liver was initially decreased after acute exposure, but the prolonged treatment doubled the amount of the P-450 hemoprotein in liver microsomes. After acute exposure 7-ethoxycoumarin 9-deethylase activity in mouse liver was doubled in 24 h. When the exposures were continued, this enhancement in ethoxycoumarin O-deethylase activity gradually disappeared. O-deethylase activity was also enhanced in rat liver and lung after subacute exposure. The exposures given had no effect on diphenyloxazole hydroxylase, and the effects on the conjugating enzymes (epoxide hydratase, UDPglucuronosyltransferase, glutathione S-transferase)) were insignificant in rat liver.
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PMID:Effects of thermal degradation products of polystyrene on drug biotransformation and tissue glutathione in rat and mouse. 73 18

Resistance to chemotherapy is a significant problem in the treatment of colorectal carcinomas. To obtain insight into the mechanism of drug resistance, the expression of P-170 glycoprotein and biotransformation enzymes that are potentially able to contribute to drug resistance were investigated in paired samples of normal mucosa and tumors from 24 patients with colorectal cancer. In the tumors, glutathione S-transferase (GST) enzyme activity and content of GST-pi and P-170 glycoprotein were increased significantly compared with normal mucosa (P less than 0.03, P less than 0.003, and P less than 0.02, respectively). In contrast, GST-alpha and -mu, present in minor amounts compared with GST-pi, were downregulated in the tumor. Cytochrome P-450(4,5,6) and UDP-glucuronyltransferase (towards 4-nitrophenol and bilirubin) levels were significantly lower in the tumors (P less than 0.0001 and P less than 0.0002, respectively). Because decreased expression of cytochrome P-450 and increased levels of GST-pi and the P-170 glycoprotein have been implicated in (multi)drug resistance, these findings strongly suggest that in colorectal tumors the inherent resistance is multifactorial. Research to overcome this resistance should therefore be directed toward a combined treatment that eliminates all of these different mechanisms.
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PMID:Expression of drug-metabolizing enzymes and P-170 glycoprotein in colorectal carcinoma and normal mucosa. 135 41

Study of drug metabolizing enzyme activity was undertaken in skin microsomal and cytosolic fractions of male and female rats. The presence of several isoforms was revealed from their activities towards selected substrates and from their cross immunoreactivity using antibodies raised against purified hepatic or renal cytochromes P-450, epoxide hydrolase and UDP-glucuronosyltransferases. Cytochrome P-450 content was precisely quantified by second derivative spectrophotometry, 23.1 and 16.5 pmol/mg protein in males and females, respectively. The monooxygenase activity associated to cytochromes P-450IIB1 and P-450IA1 was determined through O-dealkylation of ethoxy-; pentoxy- and benzoxyresorufin. The activity ranged between 4 and 2 nmol/min/mg protein for male and female rats, respectively. These results and Western blot analysis indicated that rat skin microsomes contain both monooxygenase systems associated with cytochromes P-450IIB1 and P-450IA1. By contrast lauric acid hydroxylation, supported by cytochrome P-450IVA1, was not detectable. Activities of epoxide metabolizing enzymes (microsomal and cytosolic epoxide hydrolases; glutathione S-transferase) were also characterized in skin. Microsomes catalysed the hydratation of benzo(a)pyrene-4,5-oxide and cis-stilbene oxide at the same extent, whatever the sex, although the specific activity was 10 times lower than in liver. The hydratation of trans-stilbene oxide by soluble epoxide hydrolase was four times lower than in the liver. Conjugation of cis-stilbene oxide with glutathione in skin and liver proceeded at essentially similar rates, as the specific activity of glutathione S-transferase in skin was only two times less than that measured in hepatic cytosol. Glucuronidation of 1-naphthol, bilirubin but not of testosterone could be followed in the microsomal fraction. Revelation by Western blot indicated that both the isoforms involved in conjugation of phenols and bilirubin were present in skin microsomes. By contrast, the isoform catalysing the conjugation of testosterone was apparently missing. When immunoblotting was carried out using specific antibodies raised against the renal isoforms, the same result was obtained. In addition, an intense staining corresponding to a 57 kD-protein was observed.
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PMID:Characterization of distinct forms of cytochromes P-450, epoxide metabolizing enzymes and UDP-glucuronosyltransferases in rat skin. 250 Jan 29

1. Cytochrome P-450, NADPH-cytochrome c reductase, benzo(a)-pyrene hydroxylase (AHH), 7-ethoxycoumarin-O-deethylase (7-ECOD), epoxide hydrolase (EH), UDP-glucuronyltransferase (UDPGT) and glutathione S-transferase (GSHST) activities in sturgeon (Acipenser baeri) have been measured and partially characterized. 2. Cytochrome P-450-dependent monoxygenase (MO), EH, and conjugation reactions were detected in liver and to a lesser extent in kidney and gills. 3. Hepatic enzyme activities in the sturgeon were equally high or higher than in rainbow trout liver, with the exception of UDPGT whose activity was 14% of that in trout liver. 4. The MO and EH activities displayed the expected pH maxima of 7.5, whereas transferases were relatively independent of the pH in the 6.5-7.5 range. 5. The temperature optima for MO and EH were close to those reported in other fish species, whereas for conjugation reactions the temperature optima were 45 and 60 degrees C for GSHST and UDPGT respectively.
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PMID:Characterization of xenobiotic metabolizing enzymes in sturgeon (Acipenser baeri). 250 31

Intact periportal (pp) or perivenous (pv) hepatocytes were prepared by digitonin-collagenase liver perfusion. The degree of separation was indicated by significant differences between the pp and pv cells in their activity of the pp markers, alanine aminotransferase (pp/pv = 2.1), gamma-glutamyltranspeptidase (3.4) and lactate dehydrogenase (1.3), and of the pv markers, glutamate dehydrogenase (0.73) and pyruvate kinase (0.81). This pattern was not altered by a 3-day pretreatment with phenobarbital (PB). The hepatocytes isolated from the pv area contained higher activities of microsomal NADPH-cytochrome c reductase, 7-ethoxycoumarin O-deethylase, 7-ethoxyresorufin O-deethylase and benzo(a)pyrene hydroxylase, and of cytosolic glutathione transferase. Cytochrome P-450 and UDP-glucuronosyltransferase were slightly higher in pv cells. Treatment with PB induced NADPH-cytochrome c reductase, glutathione transferase, cytochrome P-450 and UDP-glucuronosyltransferase but the degree of induction was found to be at least as strong in pp cells as in pv cells. The induction of 7-ethoxyresorufin O-deethylase and 7-ethoxycoumarin O-deethylase was clearly more prominent in pp cells. On the other hand, PB reduced the activities of benzo(a)pyrene hydroxylase and alcohol dehydrogenase in both cell types. These results demonstrate by direct enzyme assay of separated cells the dominance of the pv-region for metabolizing drugs in the normal liver. Contrary to several other studies, however, our data indicate that induction by PB occurs panacinarily, i.e., relatively more in the pp region, thus diminishing rather than exaggerating the original pv dominance.
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PMID:Effect of phenobarbital on the distribution of drug metabolizing enzymes between periportal and perivenous rat hepatocytes prepared by digitonin-collagenase liver perfusion. 302 20

In an attempt to characterize metabolism enzymes of the estrogen-induced kidney tumor in male Syrian hamsters, the activities of enzymes involved in drug and glutathione metabolism were determined in tumor tissue. Kidney tumors were induced in male Syrian hamsters by treatment with estradiol for 8 months. Cytochrome P-450 and cytochrome b5 concentrations in tumors were below detectable levels. However, when cytochrome P-450-mediated oxidation was analyzed by product formation assays, the oxidation of E-diethylstilbestrol to diethylstilbestrol-4',4"-quinone by tumor microsomes was 10-20% of the rate found in control microsomes. In kidney tissue surrounding estrogen-induced tumors, cytochrome P-450 and b5 contents were 50-60% less than those in untreated kidney. Activities of reducing enzymes of drug metabolism (cytochrome P-450, cytochrome b5 and NADH:cytochrome c reductases), glutathione metabolism enzymes (glutathione peroxidase, glutathione transferase, glutathione reductase, and gamma-glutamyl transpeptidase), and free radical scavenging enzymes (superoxide dismutase, catalase, and quinone reductase) in tumor were significantly lower than in untreated kidney tissue. The activities of these enzymes in renal tumor surrounding tissue were between those observed in tumor and control kidney. Glucose-6-phosphate dehydrogenase activity was increased by 50% in surrounding tissue and 430% in tumor compared to values in untreated controls. The decreased enzyme activity levels in hormone-exposed tissue surrounding tumors likely represented an adaptation of this tissue to the neoplastic environment induced by chronic estrogen treatment.
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PMID:Characterization of drug metabolism enzymes in estrogen-induced kidney tumors in male Syrian hamsters. 304 47

Male Sprague-Dawley rats were injected ip with benzene, toluene, or a mixture of xylene isomers at 20 mmol hydrocarbon/kg daily for 3 days. The effects of administration of these hydrocarbons upon their own in vitro metabolism, as well as upon cytochrome P-450, NADPH-cytochrome c reductase, aminopyrine N-demethylase, aniline hydroxylase, glutathione, glutathione S-transferase, and UDPglucuronyltransferase in liver were studied. Each hydrocarbon studied increased its own in vitro metabolism. Benzene had no effect on the metabolism of toluene or xylenes. Toluene and xylenes increased the metabolism of benzene, toluene, and xylenes. Cytochrome P-450 was elevated by toluene and xylenes, but was not affected by benzene. NADPH-cytochrome c reductase was induced by all three hydrocarbons. Aminopyrine N-demethylase and aniline hydroxylase were induced by toluene and xylenes and were not affected by benzene. Glutathione was elevated by benzene, decreased by xylenes, and not affected by toluene. Glutathione S-transferase was induced differentially by these hydrocarbons toward various substrates: toward 1-chloro-2,4-dinitrobenzene by benzene and toluene, toward 1,2-dichloro-4-nitrobenzene by benzene and xylenes, and no effect toward 1,2-epoxy-3-(p-nitrophenoxy)propane by any hydrocarbons. UDPglucuronyltransferase was induced by benzene and toluene when o-aminophenol and phenol were used as the substrate. Xylenes had no effect. Benzene was more effective at inducing conjugation enzymes. Xylenes were more effective at inducing cytochrome P-450 dependent enzymes. Toluene was equipotent at inducing both types of enzymes. The results indicate that the addition of methyl groups to the aromatic ring affects the inductive pattern of these monocyclic aromatic hydrocarbons.
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PMID:A comparative study of the effects of benzene, toluene, and xylenes on their in vitro metabolism and drug-metabolizing enzymes in rat liver. 308 Aug 23

These studies were designed to investigate the effects of the chrysotherapeutic agents auranofin and myochrysine (GST) on hepatic and renal drug-metabolizing enzymes and heme metabolism. Male Sprague-Dawley rats were either administered a single dose of auranofin (17, 34, or 68 mg/kg, p.o.) or administered daily doses of auranofin (0.2, 0.6, 2, 9, or 40 mg/kg/day, p.o.) or GST (1.2 or 5.8 mg/kg/day, i.p.) for 3 or 14 days. Rats were killed 24 h after the final treatment, and subcellular fractions of liver and kidney were prepared. Cytochrome P-450 (P-450) content and ethoxycoumarin-O-deethylase (ECOD), benzphetamine-N-demethylase (BPND), delta-aminolevulinic acid (ALA) synthetase, and heme oxygenase activities were determined. Twenty-four hours following single doses of auranofin, no effects on hepatic P-450, ECOD, or BPND were observed. Treatment with the positive control compounds, CoCl2 (60 mg/kg) and Co-protophorphyrin IX (33 mg/kg), produced decreases in all three variables at 24 hr. Auranofin, at 2 mg/kg, and GST treatment, at both doses, reduced hepatic P-450 and ECOD activity at 3 days. This effect was reversed with continued treatment for 14 days. BPND activity was unaffected at 3 days but was decreased at 14 days. Heme oxygenase activity was enhanced at 3 days and had returned to control activity at 14 days, while ALA synthetase was unaffected. With the exception of heme oxygenase, which was increased, renal variables were unaltered at 3 days. At 14 days, renal P-450 content was decreased in the high-dose auranofin group, heme oxygenase activity was increased in all groups, and ALA synthetase activity was elevated in high-dose auranofin animals. These data indicate that, at doses twenty times the human dose, auranofin and GST administration produced reversible decreases in hepatic and renal P-450 which may be the result of altered heme metabolism.
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PMID:Effects of the chrysotherapeutic agents auranofin and gold sodium thiomalate on hepatic and renal drug metabolism and heme metabolism. 309 30

The purpose of this work was to study the relative activities and stabilities of phase-I and phase-II drug metabolizing enzymes in incubation mixtures used in vitro genotoxicity testing in order to optimize the conditions of the assay, increase sensitivity and eliminate false negative results. Cytochrome P-450, NADPH-cytochrome P-450 (cytochrome c) reductase activity and various phase-I and phase-II enzyme activities of the drug-metabolizing system were determined in incubation mixtures used in liver microsomal assays. The behaviour of aminopyrine N-demethylase and p-nitroanisole O-demethylase activities as phase-I markers have been reported previously. Other activities measured were glutathione S-transferase, glutathione S-epoxide transferase and epoxide hydrase, and lipid peroxidation (LP) was determined. The experiments were carried out on liver S9 fractions derived from non-induced mice or mice induced with sodium phenobarbital (PB), and/or beta-naphthoflavone (beta-NF). The phase-II enzymes were much more stable (70-90% residual activity) than phase-I enzyme activities (35-60%) in all conditions tested. The residual cytochrome P-450 was approximately 70% stable and the remaining activity of NADPH-cytochrome c-reductase about 80%, indicating that this latter enzyme does not limit the rate of the monoxygenase system in these conditions. Phase-II enzymes were induced to a smaller extent (about 2 times) than in phase-I enzymes (5-6 times) by beta-NF + PB. NADPH-cytochrome c-reductase behaved as phase-II enzymes in this respect as well as for stability. LP was appreciably higher in non-induced than in induced animals. Treatment with the beta-NF + PB mixture, however, showed that induced enzymes were more stable than those obtained by simple induction with either beta-NF or PB alone. These results lead to the conclusion that prolonged incubation times in mutagenicity assays are unnecessary when considering the relative stabilities of the various phase-I and phase-II enzyme activities in the drug-metabolizing system.
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PMID:Stability of drug metabolizing enzymes during the incubation conditions of the liver microsomal assay with non-induced and induced mouse liver S-9 fractions. 311 50

Effects of eight structurally closely related substituted urea herbicides were investigated on the induction of cytochrome P-450 dependent monooxygenase enzyme complex, as well as on two conjugating enzymes after short-term treatment of rats. Liver microsomal cytochrome P-450 content was induced approximately by 50%. Cytochrome P-450 dependent monooxygenase activities showed a great variety depending on the substrate and on the herbicide. Two-18-fold induction was detected with 7-ethoxycoumarin, while up to 8-fold induction was measured with benzo(a)pyrene. Aldrin epoxidase activities were increased up to 3-fold, and aminopyrine N-demethylase activities were only slightly different from the control level. UDP-glucuronyltransferase and glutathione S-transferase activities were enhanced up to 2-fold. The results indicate that chemical structure of the related substituted urea compounds, the number of halogen substituents on their phenyl group exert a strong influence on the induction of monooxygenases.
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PMID:Induction of rat hepatic drug metabolizing enzymes by substituted urea herbicides. 392 58


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