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)

Acetaminophen (APAP)-induced nephrotoxicity is age dependent in male Sprague-Dawley rats: nephrotoxicity occurs at lower dosages of APAP in 12- to 14-month olds compared with 2- to 3-month olds. The mechanisms responsible for enhanced nephrotoxicity in 12-month-old Sprague-Dawley rats are not entirely clear, but may be related to age-dependent differences in APAP metabolism in liver and/or kidney. Major pathways of hepatic APAP metabolism include sulfation and glucuronidation; glutathione conjugation represents a pathway for detoxification of reactive oxidative APAP metabolites. The present studies were designed to quantify in vitro activity of three Phase II enzyme activities: glutathione S-transferase using 1-chloro-2,4-dinitrobenzene as substrate, UDP-glucuronyl transferase using APAP as substrate, and sulfotransferase using APAP as substrate, in subcellular fractions of liver and kidney of 3-, 12-, 18-, and 30-month-old naive male Sprague-Dawley rats. In liver, glutathione S-transferase, UDP glucuronyl transferase, and sulfotransferase activities were not significantly different in rats from 3 through 30 months of age. Renal UDP glucuronyl transferase and sulfotransferase activities were similar in rats from 3 through 30 months of age. In contrast, renal glutathione S-transferase activity was characterized by a lower Km in 12- and 30-month olds when compared with 3-month olds. These data suggest that the reduced total systemic clearance of APAP in 12-month-old male Sprague-Dawley rats previously observed cannot be attributed to age-dependent differences in hepatic APAP metabolism. In addition, it is unlikely that differences in renal APAP metabolism contribute to age-dependent APAP nephrotoxicity.
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PMID:Hepatic and renal conjugation (Phase II) enzyme activities in young adult, middle-aged, and senescent male Sprague-Dawley rats. 190 80

Acetaminophen (APAP)-induced cytotoxicity and metabolism were studied in hepatocyte cultures isolated from the rat, rabbit, dog, and monkey. Cytotoxicity was evaluated by morphological examination and by alanine aminotransferase and aspartate aminotransferase released into the cell culture medium. The toxicity results obtained by these two methods were in agreement and can be explained by the biotransformation of APAP in each species. Rat and dog hepatocyte cultures contained the most APAP-sulfate conjugates, while the rabbit, dog, and monkey hepatocyte cultures contained the most APAP-glucuronide conjugates. The percentage of APAP-glutathione conjugate was very low in all species, indicating that either very little of the toxic APAP metabolite, N-acetylbenzoquinoneimine, was formed, or in the species susceptible to N-acetylbenzoquinoneimine-induced cytotoxicity, the glutathione S-transferase activity or the amount of glutathione was low. Rabbit hepatocytes transformed the most APAP during both short and long periods of exposure. Of the four species, the dog hepatocytes exhibited the highest level of APAP-induced cytotoxicity. The sensitivity of dog hepatocytes to APAP may be due to their low conjugating enzyme activity. Rat hepatocytes utilized all three pathways of APAP-biotransformation to prevent APAP-induced cytotoxicity. Monkey hepatocyte cultures had a very large capacity to transform APAP to a glucuronide conjugate and a very high level of glutathione S-transferase activity, and therefore did not exhibit any cytotoxicity. These studies indicate that the competing pathways of APAP conjugation in hepatocyte cultures from different species explain the differences observed in APAP-induced cytotoxicity.
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PMID:Metabolism and cytotoxicity of acetaminophen in hepatocyte cultures from rat, rabbit, dog, and monkey. 198 16

The potential carcinogenic activity of acetaminophen (paracetamol, APAP) was studied in male F344 rats with pre-existing liver damage induced by a choline-devoid (CD) diet. In a short-term experiment, APAP was administered by intragastric intubation as single doses of 0.5-1.5 g/kg body wt after 4 weeks feeding of CD diet had produced fatty livers in rats. Two-thirds partial hepatectomy was performed 4 h subsequent to the initiating treatment step. After a 2 week recovery period, all rats were subjected to the selection procedure of Cayama et al. and killed at week 9 of the experiment. Quantitative analysis of placental form glutathione S-transferase (GST-P)-positive liver lesion development did not reveal any enhancement by APAP, whereas administration of a non-necrogenic dose of diethylnitrosamine (20 mg/kg body wt) in the same protocol demonstrated significant promotion, confirming the utility of the model for detection of weak carcinogenicity of chemicals. In the second long-term experiment, APAP was fed at doses of 0.45 and 0.9% for 25 weeks following 27 weeks administration of CD diet which produced liver cirrhosis in the rats. Despite a slight enhancement of focal liver lesions positive for gamma-glutamyltranspeptidase (GGT), no significant promotion of GST-P-positive altered foci or nodules was observed. In contrast, continuous feeding of CD diet or 0.5% phenobarbital treatment after generation of cirrhosis with CD diet clearly enhanced the induction of both GST-P and GGT-positive liver lesions. Thus, these results indicate that APAP does not possess significant carcinogenic activity in damaged rat liver.
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PMID:Lack of hepatocarcinogenic potential of acetaminophen in rats with liver damage associated with a choline-devoid diet. 234 65

The potential liver-tumor-initiating activity of acetaminophen (paracetamol, APAP) was investigated in male F344 rats. APAP was administered by intragastric intubation either as 10 doses of 1 g/kg body weight over 5 weeks or as a single dose of 0.5 g/kg body weight 24 h after two-thirds partial hepatectomy. These initiating treatments were followed by administration of 0.1% phenobarbital in the drinking water for 12 weeks as the promoting regimen. Quantitative examination of placental glutathione S-transferase-positive foci revealed no enhancing effect of APAP on the induction of the foci consisting of more than two positive cells with either initiating treatment. If solitary positive hepatocytes were included in the effective number of foci, 10 repeated doses of 1 g/kg APAP increased the number of foci while the validity of the single positive cells is uncertain. This dose of APAP caused centrilobular necrosis. By 32P-postlabeling, although the active metabolite of APAP formed DNA adducts when incubated with isolated DNA, no DNA adduct formation was detected in the liver of rats either fed 0.1-1.5% APAP for 1 week or given 1 g/kg by gastric intubation. These results indicate that APAP possesses no tumor-initiating activity in the rat liver.
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PMID:Study for tumor-initiating effect of acetaminophen in two-stage liver carcinogenesis of male F344 rats. 336 36

Daily treatment of male rats with high doses of Paracetamol (500 mg/kg) during spermatogenesis provokes a significant decrease of testes weight (p is less than 0.001), a significant increase of testicular cytosol glutathione transferase activity ( p is less than 0.02) and of lipid peroxides in the whole homogenate (p is less than 0.01) but not in the microsomes. These alterations could be related to a stimulation of testicular metabolism but cannot produce a biochemical lesion such as glutathione depletion since its testicular content is not modified in these experimental conditions.
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PMID:Effect of daily high doses of paracetamol given orally during spermatogenesis in the rat testes. 659 79

Paracetamol (acetaminophen) 90-150 mg.kg-1 increased the activity of serum glutathione S-transferase (GST) and yet reduced the activities of liver microsomal and homogenate GST in mice. The GST activity was dose- and time-related to paracetamol. A negative correlation was found between serum GST and liver homogenate GST, as well as between serum GST and liver microsomal GST. A good positive correlation between serum GST and serum alanine aminotransferase (AAT) was also seen. In addition, butylated hydroxyanisole (BHA) and sodium ferulate (SF) remarkably reversed the changes of serum GST and serum AAT activities in paracetamol-treated mice. These results suggested that the conjugation level in liver was decreased in paracetamol-induced hepatotoxicity in mice.
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PMID:[Effects of paracetamol on glutathione S-transferase activity in mice]. 801 73

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

The protective effects of lobenzarit, an antioxidative agent and antirheumatic drug, on the cytotoxicity of paracetamol in rat hepatocytes were studied, as well as the inhibitory effects of lobenzarit on cytochrome P-450s and glutathione S-transferases (GSTs) in rat liver. Paracetamol was selected as a model toxin, since it is known to be bioactivated by specific cytochrome P-450s presumably to N-acetyl-p-benzoquinoneimine, a reactive metabolite which upon overdosage of paracetamol causes protein and non-protein thiol depletion, lipid peroxidation and cytotoxicity measurable as LDH leakage. At concentrations of lobenzarit of 0.2 and 0.3 mM, added 30 min before paracetamol, the drug prevented paracetamol-induced leakage of lactate dehydrogenase (LDH) almost completely and lipid peroxidation (LPO) and depletion of glutathione (GSH) substantially and also the formation of the 3-glutathionyl conjugate of paracetamol. However, at a concentration of 0.05 mM Lobenzarit did not protect anymore against the paracetamol toxicity, When added to the hepatocytes 1 h and 2 h before paracetamol, 0.05 and 0.2 and 0.3 mM concentrations of lobenzarit did not protect against the cytotoxicity induced by paracetamol either. Lobenzarit did not inhibit cytochromes P-450 1A1/1A2, 2B1/2B2 and 2E1 which were measured as ethoxyresorufin O-deethylation (EROD) activity in beta-naphthoflavone-induced rat liver microsomes, as pentoxyresorufin de-pentylation (PROD) activity in phenobarbital-induced microsomes and as p-nitrophenol hydroxylation (PNPH) activity in pyrazol-induced microsomes. Lobenzarit did not show inhibition of glutathione S-transferase (GST) activity towards 1-chloro-2,4-dinitrobenzene (CDNB) in cytosol from liver of rats treated with phenobarbital, pyrazol and beta-naphthoflavone either. It is concluded that the cytoprotective effect of lobenzarit is most likely due to its antioxidant effects and/or to its ability to stimulate GSH reductase.
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PMID:Mechanism of protection of lobenzarit against paracetamol-induced toxicity in rat hepatocytes. 874 82

The effect of guaiazulene, a lipophilic azulene derivative widely found in nature, on radical-mediated processes is examined. The ability of guaizulene to inhibit rat hepatic microsomal membrane lipid peroxidation and to scavenge hydroxyl radicals, as well as to interact with 1,1-diphenyl-2-picrylhydrazyl radical (DPPH), was estimated. It was found that guaiazulene can inhibit lipid peroxidation very significantly, having an IC50 value of 9.8 microM. It can also scavenge hydroxyl radicals and interact with DPPH. The protection afforded by guaiazulene to rats with paracetamol-induced liver injury was also investigated. Paracetamol hepatotoxicity is caused by the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which causes oxidative stress and glutathione (GSH) depletion. Hepatic cytosolic protein, GSH, glutathione transferase and glutathione reductase levels are determined as indices of hepatic injury with or without the administration of guaiazulene. It was found that all parameters affected by paracetamol are restored to normal by guaiazulene treatment, while the administration of guaiazulene alone has no effect on the performed tests compared with the control values. It was concluded that the significant protection against paracetamol-induced GSH depletion and hepatic damage afforded by guaiazulene is probably connected with its antioxidant activity. A molecular mechanism of action of guaiazulene is suggested.
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PMID:Antioxidant activity of guaiazulene and protection against paracetamol hepatotoxicity in rats. 930 66

In vitro effects of widely used nonsteroidal antiinflammatory drugs (NSAIDs) and paracetamol were studied on oxidative stress-related parameters of human red blood cells (RBC). Membrane lipid integrity, activity of erythrocyte antioxidant enzymes; i.e. glutathione S-transferase (GST), selenium dependent-glutathione peroxidase (Se-GPx), and catalase (CAT), and hemolytic/stabilizing action of the drugs on erythrocyte membrane were assessed. Diclofenac, indomethacin and paracetamol at the therapeutic and higher concentrations, and dipyrone at the high concentration exerted a statistically significant inhibition on H2O2 forced erythrocytic membrane lipid peroxidation (EMLP). Increased hemolysis was observed by Na-salicylate, naproxen and ketorolac at therapeutic and higher concentrations, and by diclofenac and tiaprofenic acid at high concentrations, while the others seemed to stabilize the membrane at the same conditions. Na-salicylate inhibited GST activity at the therapeutic dose, however activated the same enzyme at high concentrations. Naproxen, tiaprofenic acid and piroxicam caused a decrease in GST activity at therapeutic doses. Paracetamol caused an activation at a high dose. Tiaprofenic acid, ketorolac, naproxen and piroxicam caused a significant Se-GPx inhibition. Erythrocyte CAT activity was increased by Na-salicylate, acemetacin, and tenoxicam at the therapeutic, and by dipyrone at the high concentration. Our results suggest that NSAIDs and paracetamol may be involved in oxidative/antioxidative processes of human erythrocytes. Also, the in vitro EMLP method can be considered as a simple test for evaluating possible antioxidant potency of chemicals.
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PMID:In vitro effects of NSAIDS and paracetamol on oxidative stress-related parameters of human erythrocytes. 1148 31


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