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)

In view of a role of oxidative stress in epilepsy and the evidence for the involvement of peroxidative injury in sodium valproate (SVP)-induced adverse effects on liver and kidneys, we investigated whether the combination of SVP with N-acetylcysteine (NAC), an antioxidant, may help us to achieve maximal efficacy in terms of seizure control, with minimal toxicity on liver and kidneys. Pentylenetetrazole (PTZ)-induced seizures were used to evaluate the anticonvulsant effect of drugs. Biochemical estimations included the determination of oxidative stress markers like thiobarbituric acid-reactive substances in brain tissue and glutathione (GSH) levels in liver and kidney tissues. Aspartate aminotransferase and alanine aminotransferase concentrations in the serum were also determined to assess liver function. In our study, NAC exhibited a nondose-dependent anticonvulsant effect. The concurrent administration of NAC with SVP significantly prolonged the latency to jerks, myoclonus and clonic generalized seizures. No significant oxidative stress was evident in brain tissue following PTZ-induced seizures, though an elevation of serum transaminase enzymes was seen. SVP at the dose studied did not produce any significant oxidative stress on the liver and kidneys, while treatment with NAC elevated liver and kidney GSH levels. The concurrent administration of NAC with SVP had beneficial effects on liver and kidney cells.
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PMID:Modulation of pentylenetetrazole-induced seizures and oxidative stress parameters by sodium valproate in the absence and presence of N-acetylcysteine. 1667 59

Acute effects of mercuric chloride (HgCl2) were evaluated on mice. Mice received a single dose of HgCl2 (4.6 mg/kg, subcutaneously) for three consecutive days. Thirty minutes after the last injection with HgCl2, mice received one single injection of 2,3-dimercapto-1-propanesulfonic acid (DMPS) or N-acetylcysteine (NAC) or diphenyl diselenide (PhSe)2. DMPS, NAC and (PhSe)2 were utilized as therapy against mercury exposure. At 24 h after the last HgCl2 injection, blood, liver and kidney samples were collected. delta-Aminolevulinate dehydratase (delta-ALA-D) and Na+, K- (+) ATPase activities, thiobarbituric acid-reactive substances (TBARS), non-protein thiols (NPSH) and ascorbic acid concentrations were evaluated. Plasma aspartate (AST) and alanine (ALT) aminotransferase activities, as well as urea and creatinine levels were determined. The group of mice exposed to Hg + (PhSe)2 presented 100% of lethality. Exposure with HgCl2 caused a decrease on the body weight gain and treatments did not modify this parameter. delta-ALA-D, AST and ALT activities, TBARS, ascorbic acid levels and NPSH (hepatic and erythrocytic) levels were not changed after HgCl2 exposure. HgCl2 caused an increase in renal NPSH content and therapies did not modify these levels. Mice treated with (PhSe)2, Hg + NAC and Hg + DMPS presented a reduction in plasma NPSH levels. Creatinine and urea levels were increased in mice exposed to Hg + NAC, while Hg + DMPS group presented an increase only in urea level. Na+, K- (+) ATPase activity was inhibited in mice exposed to Hg + DMPS and Hg + NAC. In conclusion, therapies with (PhSe)2, DMPS and NAC following mercury exposure must be better studied because the formation of more toxic complexes with mercury, which can mainly damage renal tissue.
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PMID:DMPS and N-acetylcysteine induced renal toxicity in mice exposed to mercury. 1684 Dec 48

N-acetylcysteine (NAC) is an antioxidant and cytoprotective agent with scavenging action against reactive oxygen species and inhibitory effects on pro-inflammatory cytokines. In a previous study, we found that pretreatment with NAC attenuated organ dysfunction and damage, reduced the production of free radicals, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) following endotoxemia elicited by administration of lipopolysaccharide (LPS). In the present study, we tested the effects of post-treatment with NAC on the sepsis-induced change. Post-treatment imitates clinical therapeutic regimen with administration of drug after endotoxemia. Endotoxin shock was induced by intravenous injection of Klebsiella pneumoniae LPS (10 mg/kg) in conscious rats. Mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 48 h after LPS administration. NAC was given 20 min after LPS. Measurements of biochemical substances were taken to reflect organ functions. Biochemical factors included blood urea nitrogen (BUN), creatinine (Cre), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate transferase (GOT), alanine transferase (GPT), TNF-alpha, interleukin-6 (IL-6), and interleukin-10 (IL-10). LPS significantly increased blood BUN, Cre, LDH, CPK, GOT, GPT, TNF-alpha, IL-6, IL-10 levels and HR, and decreased MAP. Post-treatment with NAC diminished the decrease in MAP, increased the HR, and decreased the markers of organ injury (BUN, Cre, LDH, CPK, GOT, GPT) and inflammatory biomarkers (TNF-alpha, IL-6, IL-10) after LPS. We conclude that post-treatment with NAC suppresses the release of plasma TNF-alpha, IL-6, and IL-10 in endotoxin shock, and decreases the markers of organ injury. These beneficial effects protect against LPS-induced kidney, heart and liver damage in conscious rats. The beneficial effects may suggest a potential chemopreventive effect of this compound after sepsis.
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PMID:Post-treatment with N-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats. 1686 Mar 47

Acute effects of mercury on mouse blood, kidneys, and liver were evaluated. Mice received a single dose of mercuric chloride (HgCl2, 4.6 mg/kg, subcutaneously) for three consecutive days. We investigated the possible beneficial effects of antioxidant therapy (N-acetylcysteine (NAC) and diphenyl diselenide (PhSe)2) compared with the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS), an effective chelating agent in HgCl2 exposure in mice. We also verified whether metallothionein (MT) induction might be involved in a possible mechanism of protection against HgCl2 poisoning and whether different treatments would modify MT levels and other toxicological parameters. The results demonstrated that HgCl2 exposure significantly inhibited delta-aminolevulinate dehydratase (delta-ALA-D) activity in liver and only DMPS treatment prevented the inhibitory effect. Mercuric chloride caused an increase in renal non-protein thiol groups (NPSH) and none of the treatments modified renal NPSH levels. Urea concentration was increased after HgCl2 exposure. NAC plus (PhSe)2 was partially effective in protecting against the effects of mercury. DMPS and (PhSe)2 were effective in restoring the increment in urea concentration caused by mercury. Thiobarbituric acid-reactive substances (TBARS), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) activities and ascorbic acid levels were not modified after mercury exposure. Mercuric chloride poisoning caused an increase in hepatic and renal MT levels and antioxidant treatments did not modify this parameter. Our data indicated a lack of therapeutic effect of the antioxidants tested.
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PMID:Antioxidants and metallothionein levels in mercury-treated mice. 1696 87

Nutraceuticals are widely used by the general public, but very little information is available regarding the effects of nutritional agents on drug toxicity. Excessive doses of acetaminophen (APAP, 4-hydroxyacetanilide) induce hepatic centrilobular necrosis. The naturally occurring substance S-adenosyl-l-methionine (SAMe) has been reported to reduce the hepatic toxicity of APAP. The present study was designed to investigate the hepatoprotective effects of SAMe in comparison to the clinically used antidote N-acetylcysteine (NAC). Male C57BL/6 mice were injected intraperitoneally (i.p.) with an equimolar dose (1.25 mmol/kg) of either SAMe or NAC just before APAP, and the groups were denoted SAMe+APAP and NAC+APAP, respectively. Mice were immediately injected i.p. with 300 mg/kg APAP, and hepatotoxicity was evaluated after 4 h. SAMe was more hepatoprotective than NAC at a dose of 1.25 mmol/kg as liver weight was unchanged by APAP injection in the SAMe+APAP group, whereas liver weight was increased in the NAC+APAP group. SAMe was more hepatoprotective for APAP toxicity than NAC, because alanine aminotransferase levels were lower in the SAMe+APAP. Pretreatment with SAMe maintained total hepatic glutathione (GSH) levels higher than NAC pretreatment before APAP, although total hepatic GSH levels were lower in the SAMe+APAP and NAC+APAP groups than the vehicle control values. Oxidative stress was less extensive in the SAMe+APAP group compared with the APAP-treated mice as indicated by Western blots for protein carbonyls and 4-hydroxynonenal-adducted proteins. In summary, SAMe reduced APAP toxicity and was more potent than NAC in reducing APAP hepatotoxicity.
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PMID:Comparison of S-Adenosyl-L-methionine and N-acetylcysteine protective effects on acetaminophen hepatic toxicity. 1706 66

Stellate cells are activated by free radicals, and synthesize collagen. N-acetylcysteine (NAC) is a precursor of reduced glutathione and a potent scavenger of hydroxyl radicals and has potential antifibrotic effects. We aimed to test the effects of NAC on bile duct ligation (BDL) induced liver damage in rats. Forty-seven Wistar rats were divided into 5 groups: group 1, BDL+NAC (n=10); group 2, BDL (n=10); group 3, sham+NAC (n=10); group 4, sham (n=10); and group 5, control group (n=10). NAC (50 micromol/kg per day) or saline of single doses were administered intraperitoneally for 28 days. Serum biochemical and liver oxidative stress parameters were studied. Liver collagen level was determined by the method of Lopez de Leon and Rojkind. Liver slides were stained by hematoxylin and eosin and Masson trichrome\Gomory reticulum staining. Aspartate aminotransferase (AST) and alkaline phosphatase levels in the BDL+NAC group were lower than the BDL group and were higher than the control groups (all P< .001). Malondialdehyde, luminal, and glutathione levels in group 1 were lower than the BDL group (P= .01, P= .002, and P< .001) and higher than the control groups (all P< .001). NAC had no effect on alanine aminotransferase (ALT), gammaglutamyl transferase, bilirubin, albumin, or lucigenin levels. Liver collagen levels were higher in the BDL groups (P< .001); however, NAC had no effect on the collagen levels. The BDL groups showed stage 3 fibrosis; all the control groups were normal. NAC improved some biochemical parameters (AST, alkaline phosphatase) and oxidative stress parameters (malondialdehyde, luminol, glutathione) in the BDL model. NAC was found to be effective on cholestasis-induced hepatotoxicity. However, NAC was inefficient as an antifibrotic agent within a 1-month period of administration in the BDL model.
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PMID:The effects of N-acetylcysteine on bile duct ligation-induced liver fibrosis in rats. 1743 97

The immunosuppressive agent cyclosporine A (CsA) has been reported to exert measurable hepatotoxic effects. One of the causes leading to hepatotoxicity is thought to be reactive oxygen radical formation. The aim of this study was to investigate the effects of N-acetylcysteine (NAC) treatment on CsA-induced hepatic damage by both analysing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), aspartate aminotransferase (AST) and alanine transaminase (ALT) activities with malondialdehyde (MDA) and nitric oxide (NO) levels, and using an histological approach. CsA administration produced a decrease in hepatic SOD activity, and co-administration of NAC with CsA resulted in an increase in SOD activity. MDA and NO levels increased in the CsA group and NAC treatment prevented those increases. A significant elevation in serum AST and ALT activities was observed in the CsA group, and when NAC and CsA were co-administered, the activities of AST and ALT were close to the control levels. CsA treatment caused evident morphological alterations. Control rats showed no abnormality in the cytoarchitecture of the hepatic parenchyma. The co-administration of NAC with CsA showed no signs of alteration and the morphological pattern was almost similar to the control group. In conclusion, CsA induced liver injury and NAC treatment prevented the toxic side effects induced by CsA administration through the antioxidant and radical scavenging effects of NAC.
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PMID:The protective effect of N-acetylcysteine against cyclosporine A-induced hepatotoxicity in rats. 1746 32

The analgesic and antipyretic drug acetaminophen (APAP) is bioactivated to the reactive intermediate N-acetyl-p-benzoquinoneimine, which is scavenged by glutathione (GSH). APAP overdose can deplete GSH leading to the accumulation of APAP-protein adducts and centrilobular necrosis in the liver. N-acetylcysteine (NAC), a cysteine prodrug and GSH precursor, is often given as a treatment for APAP overdose. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate cysteine ligase (GCL) a heterodimer composed of catalytic and modifier (GCLM) subunits. Previous studies have indicated that GCL activity is likely to be an important determinant of APAP toxicity. In this study, we investigated APAP toxicity, and NAC or GSH ethyl ester (GSHee)-mediated rescue in mice with normal or compromised GCLM expression. Gclm wild-type, heterozygous, and null mice were administered APAP (500 mg/kg) alone, or immediately following NAC (800 mg/kg) or GSHee (168 mg/kg), and assessed for hepatotoxicity 6 h later. APAP caused GSH depletion in all mice. Gclm null and heterozygous mice exhibited more extensive hepatic damage compared to wild-type mice as assessed by serum alanine aminotransferase activity and histopathology. Additionally, male Gclm wild-type mice demonstrated greater APAP-induced hepatotoxicity than female wild-type mice. Cotreatment with either NAC or GSHee mitigated the effects of APAP in Gclm wild-type and heterozygous mice, but not in Gclm null mice. Collectively, these data reassert the importance of GSH in protection against APAP-induced hepatotoxicity, and indicate critical roles for GCL activity and gender in APAP-induced liver damage in mice.
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PMID:Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice. 1758 59

The potential role of sodium sulphate in possible enhancement of the hepatoprotective action of N-acetylcysteine (NAC) in paracetamol (PCM) overdose was examined. The effects of sodium sulphate (200 mg/kg) in combination with NAC (400 mg/kg) administered intraperitoneally 2 h post-PCM dose, on mortality rate and plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were investigated in mice 24 h after receiving a single oral dose of 400 mg/kg PCM. In addition, the effect on the mortality rate of PCM-treated animals of co-administering 400 mg/kg sodium sulphate with NAC (200 or 400 mg/kg) was also studied. NAC alone caused a marked reduction in the mortality rate of PCM-treated mice and a sharp drop in their plasma AST and ALT activities to near normal values. However, no additional reduction in plasma levels of AST and ALT was observed when sodium sulphate was co-administered with NAC. Similarly, sodium sulphate (200 mg/kg) administered alone to PCM-treated mice had no effect on the high mortality rate or the elevation in plasma AST and ALT activities observed in these animals. Furthermore, increasing the dose of sodium sulphate to 400 mg/kg did not influence the mortality rate. It is therefore concluded that sodium sulphate neither protects against paracetamol-induced hepatotoxicity nor enhances the hepatoprotective action of N-acetylcysteine.
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PMID:Paracetamol-induced hepatotoxicity: lack of enhancement of the hepatoprotective effect of N-acetylcysteine by sodium sulphate. 1765 22

Previous studies have suggested that patients receiving both activated charcoal (AC) and N-acetylcysteine (NAC) after acute acetaminophen (APAP) overdoses may have improved outcomes. We evaluated all acute acetaminophen overdoses that received NAC therapy reported to US poison centers for the years 1993 through 2004. Groups were separated based on therapy received: 1) both AC and NAC and 2) NAC alone. There were 97,960 acetaminophen overdoses reported, with 49,427 patients (50%) receiving NAC and AC. Reports of AST/ALT > 1000, a major effect, and death were 1301 (2.9%), 2957 (6.6%), and 232 (0.5%), respectively, for patients receiving NAC plus AC, vs. 5273 (12%), 4534 (10.3%), and 369 (0.8%), respectively, for patients receiving NAC alone (p < 0.01). Use of Toxic Exposure Surveillance System data in the present study has a number of limitations, including its retrospective nature and no documentation of when NAC therapy was initiated. It is possible that those patients who did not receive AC presented to the Emergency Department later in their overdose and had NAC therapy initiated later, and therefore they were predisposed to a greater risk of hepatic injury. Evaluation of 12 years of acute APAP overdoses suggests that the use of AC, in addition to NAC therapy, may provide improved patient outcomes.
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PMID:Impact of activated charcoal after acute acetaminophen overdoses treated with N-acetylcysteine. 1769 65


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