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)

Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl(4)) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1). Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl(4) p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6beta-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and alpha-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration. Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A.
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PMID:Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats. 1206 33

Previous studies from this laboratory indicated that glutathione (GSH) conjugate formation with acetaminophen (APAP) is remarkably induced in liver of weanling rats in response to a single overdose of the drug administered intraperitoneally (ip). Increased APAP-GSH conjugation has been attributed to inducible glutathione S-transferases (GSTs) in dividing hepatocytes. In order to verify this finding, an in vitro reconstitution assay containing liver microsomes (source of cytochrome P-450) and cytosolic fractions (source of GST) from livers and kidneys of adult and weanling rats has been established. In vitro incubation of the reaction mixture was followed by solvent extraction, enzymatic digestion and HPLC analysis of the conjugate. Under controlled conditions, in vitro, the rate of APAP-GSH conjugation reflected the GST activity of cytosolic sample added to incubation system. The activity of cytosolic GST in catalyzing this reaction was measured using cytosols prepared from various tissue sources, particularly from animals pretreated with dietary butylated hydroxylanisole (BHA). The extent of APAP-GSH conjugate formation mediated by cytosols varied in this order: BHA-treated adult liver>BHA-treated weanling liver>control adult liver>control weanling liver>BHA-adult kidney>control adult kidney>BHA weanling kidney>control weanling kidney. In contrast to findings obtained from in vivo experiments, the rate of GST-dependent APAP conjugate formation with GSH in vitro is not induced in the presence of exogenous drug.
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PMID:Acetaminophen-glutathione conjugate formation in a coupled cytochrome P-450-glutathione S-transferase assay system mediated by subcellular preparations from adult and weanling rat tissues. 1242 44

Chronic ethanol consumption potentiates acetaminophen (APAP) hepatotoxicity through enhanced NAPQI formation via CYP2E1 induction and selective depletion of mitochondrial glutathione. Because the prevalence of the interaction is extremely low given the use of APAP and the incidence of alcohol abuse, we studied the effects of ethanol dose and ethanol withdrawal on selective mitochondrial glutathione (GSH) depletion and APAP toxicity in liver slices. Rats were fed the Lieber-DeCarli diet containing ethanol (0, 7, 18, 27, and 36% total energy) for 6 weeks. The highest ethanol-containing diet (36% energy as ethanol) was replaced by control diet for 2, 5, 12, and 17 h. Maximal CYP2E1 induction was caused by 36% energy as ethanol diet (2.2-fold, p < 0.05 versus control). The activity and liver protein content returned to the control level 17 h after ethanol withdrawal. The 36% energy as ethanol diet caused maximal mitochondrial GSH depletion (51%, p < 0.05 versus control), which was restored 17 h after ethanol withdrawal (22.0 +/- 4.9 versus 11.7 +/- 1.7 nmol/mg protein of 0 h, p < 0.01). Elevated glutathione S-transferase-alpha release in liver slices (a measure of toxicity) was observed in rats fed 36% energy as ethanol diet (1 mM APAP: 69 +/- 10 versus 3 +/- 1% of control, p < 0.01). Enhanced toxicity disappeared when ethanol dose decreased and when ethanol was removed (7.2% ethanol: 3 +/- 1% and 17 h: 2 +/- 1%, p < 0.01 versus 0 h 36% energy as ethanol). In conclusion, high-dose ethanol potentiated APAP hepatotoxicity via CYP2E1 induction and selective mitochondrial GSH depletion. Mitochondrial GSH depletion quickly reversed when ethanol was withdrawn. The time window for both mechanisms to act in concert is narrow.
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PMID:Effects of ethanol dose and ethanol withdrawal on rat liver mitochondrial glutathione: implication of potentiated acetaminophen toxicity in alcoholics. 1243 12

Rats pretreated with acetaminophen (N-acetyl-p-aminophenol, APAP) (600 mg/kg b.w., p.o.) were administered with ethanol and ethyl acetate extracts as well as with isocytisoside (100 mg/kg b.w., p.o.) obtained from Aquilegia vulgaris (L.) (Ranunculaceae) herb. The substances tested decreased enzymatic, non-enzymatic and uninduced microsomal lipid peroxidation (LPO) in the liver of rats treated with APAP by 18-48%. Activity of the antioxidant enzymes in the liver inhibited by APAP was increased in the majority of groups after administration of the substances tested: catalase (CAT) by 55%, glutathione peroxidase (GPx) by 50%, glutathione reductase (GR) by 35% and glutathione S-transferase (GST) by 60%. Hepatic glutathione level depleted by APAP was only slightly increased by the substances tested. The cytochrome P450 contents, and the activities of NADPH-cytochrome P450 reductase and two monooxygenases were not affected by the extracts and isocytisoside. It can be concluded that the protective ability of the substances tested in APAP-induced liver injury is mediated by amelioration of microsomal lipid peroxidation and restoring antioxidant enzymes activity. Inhibition of enzymes responsible for metabolic activation of APAP is not involved in this process.
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PMID:Protective effect of Aquilegia vulgaris (L.) on APAP-induced oxidative stress in rats. 1570 75

Lipid peroxidation is believed to play an important role in the pathogenesis of several diseases, such as cancer, diabetic mellitus and liver injury. Aqueous and ethanol extracts of Sargassum polycystum C. Agardh (Phaeophyta) were screened for their protective effects against acetaminophen (ACP; Paracetamol)-induced lipid peroxidation in rats. A single dose of acetaminophen significantly elevated the levels of lipid peroxides (LPO) with decreased levels of free radical scavenger enzymes (SOD, CAT, GSH, GPx, GST) in liver homogenate. The oral pretreatment of rats with ethanol and aqueous extracts of Sargassum polycystum C. Agardh (100 mg, 200 mg[sol ]kg body wt[sol ]day respectively, for a period of 15 days) significantly reduced the acetaminophen-induced oxidative stress in rats. The animals treated with the ethanol and aqueous extracts alone did not show any toxicity on liver tissue. This observation shows that the seaweed crude extracts probably acted to protect against acetaminophen-induced lipid peroxidation through their free radical scavenging property.
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PMID:Protective effect of Sargassum polycystum (brown alga) against acetaminophen-induced lipid peroxidation in rats. 1585 86

The protective effects of carvedilol, an antihypertensive agent, against oxidative injury caused by acetaminophen were studied in rat liver. Male Wistar rats (250 +/- 30 g) were pre-treated with carvedilol (3.6 mg/kg, p.o.) for 10 days and on the 11th day received an overdose of acetaminophen (800 mg/kg, p.o.). Four hours after acetaminophen administration, blood was collected to determine serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). After that, rats were killed and the livers were excised to determine reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and carbonyl protein contents, and the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST), and also the DNA damage index. Acetaminophen significantly increased the levels of TBARS, the DNA damage and SOD, AST and ALT activities. Carvedilol was able to prevent lipid peroxidation, protein carbonilation and DNA fragmentation caused by acetaminophen. Moreover, this drug prevented increases in SOD, AST and ALT activities. These results show that carvedilol exerts cytoprotective effects against oxidative injury caused by acetaminophen in rat liver. These effects are probably related to the O2*- scavenging property of carvedilol or its metabolites.
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PMID:Cytoprotective effects of carvedilol against oxygen free radical generation in rat liver. 1615 51

Nuclear receptors, including constitutive androstane receptor, pregnane X receptor, and retinoid X receptor (RXR), modulate acetaminophen (APAP)-induced hepatotoxicity by regulating the expression of phase I cytochrome P450 (P450) genes. It has not been fully resolved, however, whether they regulate APAP detoxification at the phase II level. The aim of the current study was to evaluate the role of RXRalpha in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXRalpha knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAP-induced hepatotoxicity, even though basal liver glutathione (GSH) levels were significantly lower in mutant mice compared with those of wild-type mice. High-performance liquid chromatography analysis of APAP metabolites revealed significantly greater levels of APAP-GSH conjugates in livers and bile of mutant mice compared with those of wild-type mice. Furthermore, hepatocyte RXRalpha deficiency altered the gene expression profile of the glutathione S-transferase (Gst) family. Basal expression of 13 of 15 Gst genes studied was altered in hepatocyte-specific RXRalpha-deficient mice. This probably led to enhanced APAP-GSH conjugation and reduced accumulation of N-acetyl-p-benzoquinone imine, a toxic electrophile that is produced by biotransformation of APAP by phase I P450 enzymes. In conclusion, the data presented in this study define an RXRalpha-Gst regulatory network that controls APAP-GSH conjugation. This report reveals a potential novel strategy to enhance the detoxification of APAP or other xenobiotics by manipulating Gst activity through RXRalpha-mediated pathways.
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PMID:Retinoid X receptor alpha Regulates the expression of glutathione s-transferase genes and modulates acetaminophen-glutathione conjugation in mouse liver. 1615 96

The effect of the inducible forms of 70 kDa heat shock protein (Hsp70i) on acetaminophen (APAP) hepatotoxicity was assessed in an Hsp70i knockout mouse model. Absence of the Hsp70i protein in liver was verified by monitoring Hsp levels in knockout and control mice after heat stress (41.5 degrees C water bath immersion for 30 min). Hsp70i knockout mice were more susceptible to APAP-induced hepatotoxicity than controls, as indicated by elevated serum alanine aminotransferase activities 24 and 48 h after the APAP dose. Increased APAP hepatotoxicity in knockout mice was verified by morphological evaluation of liver sections. The difference in toxic response to APAP between knockout and control strain mice could not be attributed to differences in APAP bioactivation, assessed by measurement of CYP2E1 and glutathione S-transferase activities, hepatic nonprotein sulfhydryl content, or covalent binding of reactive APAP metabolites to proteins. Pretreatment with transient hyperthermia to produce a general upregulation of Hsps resulted in decreased APAP hepatotoxicity in both the knockout and control strains. Among thermally-pretreated mice, hepatotoxicity of APAP was greater in the knockouts compared with the control strain. These observations suggest that increased Hsp70i expression in response to APAP acts to limit the extent of tissue injury. Results further suggest that other factors related to heat stress can also contribute to protection against APAP toxicity.
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PMID:Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice. 1628 Jan 47

Several in-vitro and in-vivo ethnopharmacological studies carried out with plants of the genus Wedelia have already demonstrated hepatoprotective effects in chemically-induced liver injury, including those induced by paracetamol. Here, the effects of the crude extract from Wedelia paludosa on paracetamol-induced hepatotoxicity in mice was investigated. Intraperitoneal injection of paracetamol (1,000 mg kg(-1)) caused 80% death after 24 h in mice, which was significantly reduced by oral pretreatment with W. paludosa (500 mg kg(-1)). Hepatotoxicity was observed 24 h after an intraperitoneal injection of paracetamol (600 mg kg(-1)), as evidenced by an increase in plasma activity of aspartate and alanine aminotransferases. That hepatotoxicity was significantly attenuated by W. paludosa pretreatment (100-500 mg kg(-1)) in a dose-response manner. Paracetamol (1,000 mg kg(-1)) drastically depleted total glutathione levels and decreased glutathione peroxidase and delta-aminolevulinate dehydratase activity in the liver, such effects not being prevented by pretreatment with W. paludosa. Neither paracetamol treatment alone nor pretreatment with W. paludosa altered glutathione reductase and glutathione S-transferase activity or the levels of end-products of lipid peroxidation. In conclusion, we found that W. paludosa protected against paracetamol-induced hepatotoxicity, an effect not observed over oxidative stress-related parameters. Hepatoprotection is likely mediated by some terpenes present in W. paludosa extract. However, further studies will be required to explain the mechanisms involved in the hepatoprotection afforded by W. paludosa.
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PMID:Protective effect of crude extract from Wedelia paludosa (Asteraceae) on the hepatotoxicity induced by paracetamol in mice. 1639 74

Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.
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PMID:Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation. 1762 Mar 48


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