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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that following a toxic dose of acetaminophen to mice, tyrosine nitration occurs in the protein of cells that become necrotic. Nitration of tyrosine is by peroxynitrite, a species formed from nitric oxide (NO) and superoxide. In this manuscript we studied the effects of the NO synthase inhibitors N-monomethyl-l-arginine (l-NMMA), N-nitro-l-arginine methyl ester (NAME), l-N-(1-iminoethyl)lysine (l-NIL), and aminoguanidine on acetaminophen hepatotoxicity. Acetaminophen (300 mg/kg) increased serum nitrate/nitrite and alanine aminotransferase (ALT) levels, indicating increased NO synthesis and liver necrosis, respectively. None of the NO synthase inhibitors reduced serum ALT levels. In fact, l-NMMA, l-NIL, and aminoguanidine significantly augmented acetaminophen hepatotoxicity at 4 h. A detailed time course indicated that aminoguanidine (15 mg/kg at 0 h and 15 mg/kg at 2 h) significantly increased serum ALT levels over that for acetaminophen alone at 2 and 4 h; however, at 6 and 8 h serum ALT levels in the two groups were identical. At 2 h following acetaminophen plus aminoguanidine NO synthesis was significantly increased; however, at 4, 6, and 8 h NO synthesis was significantly decreased. Aminoguanidine also decreased acetaminophen-induced nitration of tyrosine. Acetaminophen alone did not induce lipid peroxidation, but acetaminophen plus aminoguanidine significantly increased hepatic lipid peroxidation (malondialdehyde levels) at 2, 4, and 6 h. These data are consistent with NO having a critical role in controlling superoxide-mediated lipid peroxidation in acetaminophen hepatotoxicity. Thus, acetaminophen hepatotoxicity may be mediated by either lipid peroxidation or by peroxynitrite.
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PMID:Effect of inhibitors of nitric oxide synthase on acetaminophen-induced hepatotoxicity in mice. 1189 Jul 40

Acetaminophen-induced hepatotoxicity has been attributed to covalent binding of the reactive metabolite N-acetyl-p-benzoquinone imine to cysteine groups on proteins as an acetaminophen-cysteine conjugate. We report a high-performance liquid chromatography with electrochemical detection (HPLC-ECD) assay for the conjugate with increased sensitivity compared with previous methods. Previous methods to quantitate the protein-bound conjugate have used a competitive immunoassay or radiolabeled acetaminophen. With HPLC-ECD, the protein samples are dialyzed and then digested with protease. The acetaminophen-cysteine conjugate is then quantified by HPLC-ECD using tyrosine as an internal reference. The lower limit of detection of the assay is approximately 3 pmol/mg of protein. Acetaminophen protein adducts were detected in liver and serum as early as 15 min after hepatotoxic dosing of acetaminophen to mice. Adducts were also detected in the serum of acetaminophen overdose patients. Analysis of human serum samples for the acetaminophen-cysteine conjugate revealed a positive correlation between acetaminophen-cysteine conjugate concentration and serum aspartate aminotransferase (AST) activity or time. Adducts were detected in the serum of patients even with relatively mild liver injury, as measured by AST and alanine aminotransferase. This assay may be useful in the diagnostic evaluation of patients with hepatotoxicity of an indeterminate etiology for which acetaminophen toxicity is suspect.
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PMID:Determination of acetaminophen-protein adducts in mouse liver and serum and human serum after hepatotoxic doses of acetaminophen using high-performance liquid chromatography with electrochemical detection. 1190 Oct 99

We investigated the influence of acetaminophen (APAP), an analgesic and hepatotoxic agent, on the immune system in mice. The activity of serum glutamic-pyruvic transaminase was markedly increased by about 200 fold compared to that of the vehicle control following intraperitoneal injection of 400 mg/kg of APAP. In vivo antibody-producing responses to SRBC was significantly inhibited by APAP in a dose-dependent manner, while in vivo T cell-independent antibody-producing responses to TNP-Ficoll was not inhibited. The addition of thymocytes from APAP-treated mice suppressed the response to SRBC in vitro. Thymocyte blastogenesis following mitogenic stimulation with concanavalin A was also inhibited by injection of APAP. The delayed-type hypersensitivity response and mixed lymphocyte reaction, which are used to evaluate cell-mediated immunity, were also significantly reduced after treatment with APAP. These results indicate that APAP suppresses the humoral and cell-mediated immune responses at a dose that causes liver injury.
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PMID:Acetaminophen-induced immunosuppression associated with hepatotoxicity in mice. 1191 15

When a patient with acetaminophen overdose arrives in the emergency room more than 14 hours after ingestion, the value of N-acetylcysteine is unproven and patient mortality is at least 10%. Anecdotal case reports have indicated benefit of extracorporeal detoxification of these late-arriving patients with acetaminophen overdose. We identified 10 patients with serious acetaminophen overdose, 8 that arrived in the emergency room 16 to 44 hours after acetaminophen overdose with plasma levels predicting severe hepatic toxicity, and 2 that arrived in the emergency room 8 to 12 hours after overdose but with exceedingly high levels. All patients developed severe hepatitis (mean peak alanine aminotransferase, 4,052; mean peak protime, 25 seconds). At 16 to 68 hours after overdose, the patients were treated for 4 to 6 hours with the Liver Dialysis System (Hemocleanse Inc, W. Lafayette, IN), a single-access hemodiabsorption system indicated for treatment of serious drug overdose and for treatment of hepatic encephalopathy. Acetaminophen levels fell an average of 73% during treatment. Treatment was repeated 24 or 48 hours later if acetaminophen was still measurable in plasma. All 10 patients recovered intrinsic liver function and general health, with liver enzymes starting to normalize 24 hours after treatment, and were discharged 3 to 7 days after overdose. No patient required liver transplant. Because market introduction of Liver Dialysis, there have been 40 more patients with acetaminophen-induced hepatotoxicity treated with Liver Dialysis. All have recovered liver function without long-term sequelae. Though most of these patients with already established hepatic toxicity from acetaminophen would recover without extracorporeal blood therapy, treatment with the Liver Dialysis System should assure recovery from acute hepatic failure, and may shorten the clinical course of the illness.
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PMID:Treatment of acetaminophen-induced hepatitis and fulminant hepatic failure with extracorporeal sorbent-based devices. 1192 6

Acetaminophen (AAP) overdose can cause severe liver injury and liver failure in experimental animals and humans. Recently, several authors proposed that apoptosis might be a major mechanism of cell death after AAP treatment. To address this controversial issue, we evaluated a detailed time course of liver injury after AAP (300 mg/kg) in fasted C3Heb/FeJ mice. Apoptotic hepatocytes were quantified in H&E-stained liver sections using morphologic criteria (cell shrinkage, chromatin condensation and margination, and apoptotic bodies). The number of apoptotic hepatocytes remained at baseline (0.2 +/- 0.1 cells/10 high-power fields [HPF]) up to 2 h after AAP administration. However, between 3 and 24 h, apoptotic cell death increased significantly, e.g., 6.3 +/- 0.8 cells/10 HPF at 6 h. Despite the increase in the number of hepatocytes meeting the morphological criteria of apoptosis, this cell fraction remained well below 1% of all parenchymal cells. No evidence for caspase-3 processing or increase in enzyme activity was detected at any time. These results were compared to the overall percent of necrotic cells in liver sections. Confluent areas of centrilobular necrosis were estimated to involve 40-60% of all hepatocytes between 3 and 24 h after AAP administration. These numbers correlated with the increase in plasma alanine aminotransferase activities, which reached a peak level of 5900 +/- 1350 U/l at 24 h. A similar result was obtained with higher doses of AAP and with the use of fed animals. Thus, oncotic necrosis and not apoptosis is the principal mechanism of liver-cell death after AAP overdose in vivo.
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PMID:Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? 1201 92

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

Rutin, a well-known flavonoid was investigated for its possible protective effect against paracetamol- and CCl(4)-induced hepatic damage. Paracetamol produced 100% mortality at the dose of 1 g/kg in mice while pre-treatment of animals with rutin (20 mg/kg) reduced the death rate to 40%. Oral administration of a sub-lethal dose of paracetamol (640 mg/kg) produced liver damage in rats as manifested by the rise in serum level of transaminases (AST and ALT). Pre-treatment of rats with rutin (20 mg/kg) prevented the paracetamol-induced rise in serum enzymes. The hepatotoxic dose of CCl(4) (1.5 ml/kg; orally) also raised the serum AST and ALT levels. The same dose of rutin (20 mg/kg) was able to prevent the CCl(4)-induced rise in serum enzymes. Rutin also prevented the CCl(4)-induced prolongation in pentobarbital sleeping time confirming its hepatoprotectivity. These results indicate that rutin possesses hepatoprotective activity and the presence of this compound in Artemisia scoparia may explain the folkloric use of the plant in liver damage.
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PMID:Protective effect of rutin on paracetamol- and CCl4-induced hepatotoxicity in rodents. 1249 Feb 12

The liver-selective nitric oxide (NO) donor, O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P-450 enzymes to release NO in the liver, and is shown to protect the liver from tumor necrosis factor alpha (TNF-alpha)-induced apoptosis and D-glactosamine/endotoxin-induced hepatotoxicity. This study was undertaken to examine the effects of V-PYRRO/NO on acetaminophen-induced hepatotoxicity in mice. Mice were given V-PYRRO/NO via osmotic pumps (1.8-5.4 mg/mL, 8 microL/h) 4 to 16 hours before a hepatotoxic dose of acetaminophen (600 mg/kg, intraperitoneally [ip]). V-PYRRO/NO administration dramatically reduced acetaminophen-induced hepatotoxicity in a dose- and time-dependent manner, as evidenced by reduced serum alanine aminotransferase (ALT) activity, reduced hepatic congestion, apoptosis, and improved hepatocellular pathology. The protection afforded by V-PYRRO/NO does not appear to be caused by a decrease in the formation of toxic acetaminophen metabolites, which consumes glutathione (GSH), because V-PYRRO/NO did not alter acetaminophen-induced hepatic GSH depletion. Acetaminophen-induced lipid peroxidation, as determined by the concentrations of 4-hydroxyalkenals (4-HNE) and malondialdehyde (MDA), was reduced significantly by V-PYRRO/NO treatment. Although pretreatment was most effective, administration of V-PYRRO/NO simultaneously with acetaminophen also was able to reduce acetaminophen hepatotoxicity. Genomic analysis of the liver samples 10 hours after acetaminophen intoxication showed the enhanced expression of genes associated with stress/oxidative stress, apoptosis/cell death, and DNA damage/repair. Acetaminophen-induced alterations in gene expression were attenuated significantly by V-PYRRO/NO. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western-blot analysis confirmed microarray results. In conclusion, V-PYRRO/NO is effective in blocking acetaminophen-induced hepatotoxicity in mice. This protection may involve the reduction of oxidative stress, the inhibition of apoptosis, and possibly the maintenance of hepatic vasculature to prevent congestion.
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PMID:The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. 1254 Jul 82

Streptozotocin (STZ)-induced diabetic (DB) mice challenged with single ordinarily lethal doses of acetaminophen (APAP), carbon tetrachloride (CCl4), or bromobenzene (BB) were resistant to all three hepatotoxicants. Mechanisms of protection against APAP hepatotoxicity were investigated. Plasma alanine aminotransferase, aspartate aminotransferase, and liver histopathology revealed significantly lower hepatic injury in DB mice after APAP administration. HPLC analysis of plasma and urine revealed lower plasma t1/2, increased volume of distribution (Vd), and increased plasma clearance (CLp) of APAP in the DB mice and no difference in APAP-glucuronide, a major metabolite in mice. Interestingly, covalent binding of 14C-labeled APAP to liver target proteins; arylation of APAP to 58, 56, and 44 kDa acetaminophen binding proteins (ABPs); and glutathione (GSH) depletion in the liver did not differ between nondiabetic (non-DB) and DB mice in spite of downregulated hepatic microsomal CYP2E1 and 1A2 proteins in the DB mice, known to be involved in bioactivation of APAP. Compensatory cell division measured via 3H-thymidine pulse labeling and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) indicated earlier onset of S-phase in the DB mice after exposure to APAP. Antimitotic intervention of liver cell division by colchicine (CLC) after administration of APAP led to significantly higher mortality in the DB mice suggesting a pivotal role of liver cell division and tissue repair in the protection afforded by diabetes. In conclusion, the resistance of DB mice against hepatotoxic and lethal effects of APAP appears to be mediated by a combination of enhanced APAP clearance and robust compensatory tissue repair.
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PMID:Type 1 diabetic mice are protected from acetaminophen hepatotoxicity. 1270 Apr 23

Acetaminophen (AA) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis and nephrotoxic effects in both humans and experimental animals. It has been reported that the toxic effects of AA are the result of oxidative reactions that take place during its metabolism. In this study we investigated if melatonin, vitamin E or N-acetylcysteine (NAC) are protective against AA toxicity in mice. The doses of the antioxidants used were as follows: melatonin (10 mg/kg), vitamin E (30 mg/kg) and NAC (150 mg/kg). Blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels in blood, and glutathione (GSH), malondialdehyde (MDA), oxidized protein levels and myeloperoxidase (MPO) activity in liver and kidney tissues were measured. BUN and serum creatinine, ALT and AST levels which were increased significantly following AA treatment decreased significantly after pretreatment with either vitamin E, melatonin or NAC; however, they were not reduced to control levels. ALT and AST levels were significantly higher at 4 hr compared with the 24 hr levels after AA administration. However, BUN and creatinine levels were significantly elevated only at 24 hr. GSH levels were reduced while MDA, MPO and oxidized protein levels were increased significantly following AA administration. These changes were reversed by pretreatment with either melatonin, vitamin E or NAC. Liver toxicity was higher at 4 hr, whereas nephrotoxicity appeared to be more severe 24 hr after treatment with AA. Vitamin E was the least efficient agent in reversing AA toxicity while melatonin, considering it was given as at lower dose than either vitamin E or NAC, was the most effective. This may be the result of the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes.
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PMID:Protective effects of melatonin, vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: a comparative study. 1282 15


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