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)

Male mice were treated with structurally diverse herbicides to study their effect on liver xenobiotic-metabolizing enzymes. Chlorfiurecol, trifluralin, alachlor, propham, MCPP and 2,4-DP caused increases in phase I (cytochrome P-450, ethoxycoumarin O-deethylase, and/or aminopyrine N-demethylase) and phase II (microsomal epoxide hydrolase and cytosolic glutathione S-transferase) activities. MCPP and 2,4-DP also increased cytosolic epoxide hydrolase and carnitine acetyltransferase activities suggestive of peroxisome proliferation. Benthiocarb and molinate increased only some phase II enzyme activities. Dicamba, at the dose employed, caused mortality and decreases in some of the enzymes monitored. Most of the herbicides tested induced xenobiotic-metabolizing enzyme activities, the pattern of induction being dependent on herbicide structure.
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PMID:The effect of structurally divergent herbicides on mouse liver xenobiotic-metabolizing enzymes (P-450-dependent mono-oxygenases, epoxide hydrolases and glutathione S-transferases) and carnitine acetyltransferase. 175 24

When mice were exposed to 1% 2-ethylhexanoic acid in the diet, cytosolic and microsomal epoxide hydrolase (EC 3.3.2.3) activities were increased maximally (2-2.5- and 0.5-1-fold, respectively) after 3 days. Immunochemical quantitation of these enzymes indicated that the process involved was a true induction in both cases. Maximal levels of peroxisome proliferation (as indicated by carnitine acetyltransferase activity) were obtained after 7 days of exposure. All three of these activities returned to control levels within 4 days after termination of the treatment. The liver somatic index was slightly increased after 4 days of administration of 1% 2-ethylhexanoic acid, but the protein contents of the "mitochondrial," microsomal, and cytosolic fractions were unaffected. The activity of peroxisomal palmitoyl-CoA beta-oxidation was increased 2-fold, whereas peroxisomal catalase activity was unaffected. Exposure to 2-ethylhexanoic acid also increased cytochrome oxidase activity, suggesting an effect on mitochondria. Other parameters of detoxication--i.e. total microsomal cytochrome P-450 content, cytosolic glutathione transferase activity toward 1-chloro-2,4-dinitrobenzene, and the "cytosolic" epoxide hydrolase activity localized in the "mitochondrial" fraction--were not affected by 4 days of treatment with 1% 2-ethylhexanoic acid.
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PMID:Characterization of the induction of cytosolic and microsomal epoxide hydrolases by 2-ethylhexanoic acid in mouse liver. 288 46

The effects of dietary exposure to 0.125% (w/w) p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid or 2,4,5-trichlorophenoxyacetic acid on the content of peroxisomes and levels of certain xenobiotic-metabolizing enzymes in mouse liver have been investigated. In agreement with the literature on rat liver 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid were found to cause extensive proliferation of peroxisomes (as judged by the total levels of "mitochondrial" protein, carnitine acetyltransferase, cyanide-insensitive palmitoyl-CoA oxidation and catalase) in mouse liver. On the other hand, exposure to p-chlorophenoxyacetic acid did not significantly affect any of these parameters. As with certain other peroxisome proliferators, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid increased total cytochrome oxidase activity as well. In addition, dietary exposure to 2,4-dichlorophenoxyacetic acid and to 2,4,5-trichlorophenoxyacetic acid resulted in increases in the activities of cytosolic and microsomal epoxide hydrolases in mouse liver and generally less pronounced increases in the total cytosolic glutathione transferase activity and microsomal content of cytochrome P-450. In the case of cytochrome P-450, this process can be said to be a true induction (i.e. the amount of enzyme protein is increased), because the assay procedure for cytochrome P-450 measures holoenzyme amount. Immunoquantitation demonstrated that this was also the case for the changes in cytosolic epoxide hydrolase. The dramatic differences in proliferation of peroxisomes and induction of xenobiotic-metabolizing enzymes seen here with compounds differing relatively little in structure may indicate that a receptor mechanism of some kind is involved.
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PMID:Induction of cytosolic and microsomal epoxide hydrolases and proliferation of peroxisomes and mitochondria in mouse liver after dietary exposure to p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. 303 97

Ammonium perfluorooctanoate (APFO) is known to induce a striking hepatomegaly in rats. The purpose of these studies was to determine the causes of the hepatomegaly and compare the effect to other liver-enlarging compounds. Since the total hepatic DNA content was similar in control and APFO-treated rats, the hepatomegaly represented a hypertrophic rather than a hyperplastic response. The cytochrome P-450 content and activity of benzphetamine N-demethylase increased in the livers of APFO-treated rats, indicating the proliferation of the smooth endoplasmic reticulum. In contrast to the membrane-bound enzymes, the soluble enzymes glutathione S-transferase and UDPglucuronyltransferase were unaffected by APFO treatment. The activity of carnitine acetyltransferase was disproportionately increased relative to carnitine palmitoyltransferase in the livers of APFO vs that in control rats, confirming the predominant proliferation of peroxisomes vs that of mitochondria. Morphological studies confirmed the proliferation of the endoplasmic reticulum, mitochondria, and peroxisomes in the livers of APFO-treated rats. In contrast to many other peroxisome proliferating agents, APFO did not possess hypolipidemic activity.
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PMID:Biochemical and morphological studies of ammonium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation. 360 46

The hepatic tumorigenicity of CI-924 (5,5'-(1,1'-biphenyl)-2,5-diylbis(oxy)(2,2-dimethylpentanoic acid)), a hypolipidemic agent, was evaluated in 50 B6C3F1 mice/sex/dose given drug in the diet at 0, 5, 25, and 75 mg/kg/day for 2 yr. Peroxisomal and drugmetabolizing enzyme determinations, as well as ultrastructural evaluations, were conducted in subsets of these same groups, because drugs of this class cause peroxisome proliferation and hepatic tumors in rodents. CI-924 elicited dose-dependent increases in the incidence of hepatocellular adenomas and carcinomas in both sexes that were statistically significant at 75 mg/kg. Stereologic evaluation revealed significant increases in hepatocellular peroxisome volume ratio, due to increased numbers of peroxisomes, in females at all doses and males at 75 mg/kg. Peroxisomal enzyme activity measurements revealed no change in catalase, but dose-dependent increases in carnitine acetyltransferase and cyanide-insensitive beta-oxidation in both sexes. Peroxisome proliferation, determined biochemically or ultrastructurally, was twice as great in females compared to males. Total cytochrome P-450 was increased in both sexes given 75 mg/kg. There were dose-dependent decreases in glutathione S-transferase in males and increased glutathione peroxidase in both sexes at 25 and 75 mg/kg. In conclusion, this study demonstrated that while CI-924 induced hepatic tumors in male and female B6C3F1 mice the associated peroxisome proliferation, while moderate in females, was only weak in the males after 2 yr of exposure.
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PMID:Hepatotumorigenicity and peroxisome proliferation induced by the hypolipidemic CI-924 in a two-year study in male and female B6C3F1 mice. 873 81

Phthalates are widely used as a plasticizer and cause a peroxisome proliferation. Peroxisome proliferators (PPs), such as di-2-ethylhexyl phthalate (DEHP) and clofibrate (CF) are known to have a hepatocarcinogenic potential in rodents. It has been proposed that these PPs may cause hepatocellular cancer by an oxidative damage-mediated mechanism(s). The primary purpose of this study is to find whether there is a difference between the oxidative damage by hepatocarcinogenic PPs (DEHP and CF) and the oxidative damage by weak PPs [di-n-butyl phthalate (DBP) and n-butylbenzyl phthalate (BBP)]. The second purpose is to investigate if phthalates can affect the phase I/phase II enzymes, and if the effect of PPs on metabolizing enzymes correlates with peroxisome proliferation or not. After rats were treated with PPs (DEHP, DBP and BBP; 50, 200, 1000 mg/kg, CF; 100 mg/kg, p.o., for 14 days), the activities of metabolizing enzymes and peroxisomal enzymes were investigated, and the oxidative damage was measured using 8-hydroxydeoxyguanosine (8-OHdG) in the DNA and malonedialdehyde (MDA) in the livers. These four PPs significantly increased the relative liver weights, palmitoyl-CoA oxidation and activity of carnitine acetyltransferase. DEHP was found to be the most potent PP among three phthalates. A dramatic and dose-dependent increase in hepatic MDA levels was observed in CF (100 mg/kg), DEHP (>or=50 mg/kg), DBP and BBP (>or=200 mg/kg) groups. However, the 8-OHdG in hepatic DNA was increased only in DEHP (1000 mg/kg) and CF groups. Activities of cytochrome p4501A1, 1A2, 3A4, UDP-glucuronosyl transferase and glutathione S-transferase were decreased overall by PPs, but there is no correlation between the inhibitory effect on metabolizing enzymes and the peroxisome proliferation. These results indicate that 8-OHdG positively correlates with carcinogenic potential of PPs, but other factors as well as peroxisomal H(2)O(2) could be involved in the generation of 8-OHdG and the carcinogenesis of PPs. The present findings also demonstrate that the effect of PPs on xenobiotic metabolizing enzymes may be independent of the peroxisome proliferation and the oxidative stress. Thus it is possible that the PPs affect the hepatic toxification/detoxification capacity even in humans.
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PMID:Comparison of oxidative stress and changes of xenobiotic metabolizing enzymes induced by phthalates in rats. 1463 Jan 34

To clarify whether oxidative stress is involved in the development of hepatocellular preneoplastic foci induced by fenofibrate (FF), a peroxisome proliferator-activated receptor alpha agonist, male F344/N rats were fed a diet containing 6,000, 3,000, or 0 ppm of FF for 13 weeks after N-diethylnitrosamine initiation. Two-third partial hepatectomy was performed 1 week after the FF treatment. Histopathologically, the number of hepatocellular altered foci significantly increased in the FF-treated groups with a concomitant increase in the number of hepatocytes positive for anti-Ki-67 antibody, but the number and area of glutathione S-transferase placental form (GST-P)-positive foci decreased in these groups, as compared to those in the controls. Microarray analysis or quantitative real-time reverse transcription-polymerase chine reaction demonstrated the significant up-regulations of Aco and Cyp4a1 (genes related to lipid metabolism); Gpx2, Yc2, Cat, Cyp2b15, and Ugt1a6 (metabolic oxidative stress-related genes); Apex1, Mgmt, Xrcc5, Nbn, and Gadd45a (DNA repair-related genes); and Ccnd1 (cell cycle-related genes) in the FF-treated groups, and the significant down-regulations of Cyp1a2, Gsta2, Gstm2, and Gstm3 (phase I or II metabolism-related genes); Mlh1 and Top1 (DNA repair-related genes); and Cdkn1a, Cdkn1b, Chek2, and Gadd45b (cell cycle/apoptosis-related genes) in these rats. FF-treatment increased the activity of enzymes such as carnitine acetyltransferase, carnitine palmitoyltransferase, fatty acyl-CoA oxidizing system, and catalase in the liver, but not superoxide dismutase in the liver. In addition, 8-OHdG level in liver DNA, lipofuscin deposition in hepatocytes, and in vitro reactive oxygen species production in microsomes significantly increased due to FF treatment. These results suggest that oxidative stress is involved in the development of FF-induced hepatocellular preneoplastic foci in rats.
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PMID:Possible involvement of oxidative stress in fenofibrate-induced hepatocarcinogenesis in rats. 1825 20

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