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)

The effects of the dietary antioxidant N-acetylcysteine (NAC) on alcoholic liver damage were examined in a total enteral nutrition (TEN) model of ethanol toxicity in which liver pathology occurs in the absence of endotoxemia. Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, and elevated ALT in the absence of increased expression of the endotoxin receptor CD 14, a marker of Kupffer cell activation by LPS. In addition, ethanol treatment induced CYP 2 E1 and increased TNFalpha and TGFbeta mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression. Ethanol treatment also resulted in the hepatic accumulation of malondialdehyde (MDA) and hydroxynonenal (HNE) protein adducts, decreased antioxidant capacity, and increased antibody titers toward serum hydroxyethyl radical (HER), MDA, and HNE adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation, and inhibited the formation of antibodies toward HNE and HER adducts without interfering with CYP 2 E1 induction. NAC also decreased ethanol-induced ALT release and inflammation and prevented significant loss of hepatic GSH content. However, the improvement in necrosis score and reduction of TNFalpha mRNA elevation did not reach statistical significance. Although a direct correlation was observed among hepatic MDA and HNE adduct content and TNFalpha mRNA expression, inflammation, and necrosis scores, no correlation was observed between oxidative stress markers or TNFalpha and steatosis score. These data suggest that ethanol-induced oxidative stress can contribute to inflammation and liver injury even in the absence of Kupffer cell activation by endotoxemia.
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PMID:Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition. 1608 80

Primary cultures of rat hepatocyte and rats were used as the in vitro and in vivo models to evaluate the hepatoprotective activity of aqueous extract from Thunbergia laurifolia (TLE). Ethanol was selected as hepatotoxin. Silymarin (SL) was the reference hepatoprotective agent. In the in vitro study, MTT reduction assay and release of transaminases (ALT and AST) were the criteria for cell viability. Primary cultures of rat hepatocyte (24 h culturing) were treated with ethanol (96 microl/ml) and various concentrations of TLE (2.5, 5.0, 7.5 and 10.0 mg/ml) or SL (1, 2 and 3 mg/ml) for 2 h. Ethanol decreased MTT (%) nearly by half. Both TLE and SL increased MTT reduction and brought MTT (%) back to normal. Ethanol induced release of ALT and AST was also reduced by TLE (2.5 and 5.0 mg/ml) and SL (1 mg/ml). In the in vivo study, serum transaminases, serum triglyceride (STg) together with hepatic triglyceride (HTg) and histopathological examination were the criteria for evidences of liver injury. Ethanol (4 g/(kg day), po for 14 days) caused the increase in ALT, AST, HTg and centrilobular hydropic degeneration of hepatocytes. TLE at 25 mg/(kg day), po, or SL at 5 mg/(kg day), po, for 7 days after ethanol enhanced liver cell recovery by bringing HTg, ALT and/or AST back to normal. These results suggest that TLE and SL possess the hepatoprotective activity against ethanol induced liver injury in both primary cultures of rat hepatocyte and rats.
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PMID:Hepatoprotective activity of Thunbergia laurifolia Linn extract in rats treated with ethanol: in vitro and in vivo studies. 1608 78

Ursolic acid is a triterpenoid that exists in nature and is the major component of some traditional medicinal herbs. In this study, ursolic acid has been evaluated for its hepatoprotective effect against chronic ethanol-mediated toxicity in rats. Ethanol administration (7.9 g/kg/day) for 60 days resulted in increased oxidative stress, decreased antioxidant defense and liver injury. It also negatively affected the serum total protein, albumin and A/G ratio. Subsequent to the experimental induction of toxicity (i.e. after the initial period of 30 days) ursolic acid treatment performed by co-administering ursolic acid (10, 20 and 40 mg/kg body weight) for 30 days along with the daily dose of ethanol. While this treatment causing a significant improvement in body weight, food intake and serum protein levels, it decreases serum aminotransferase activities (aspartate aminotransferase and alanine aminotransferase) and total bilirubin levels. Ursolic acid improved the antioxidant status of alcoholic rats, which is evaluated by the decreased levels of lipid peroxidation markers in plasma (thiobarbituric acid reactive substances and lipid hydroperoxides) and increased levels of circulatory antioxidants such as reduced glutathione, ascorbic acid and alpha-tocopherol. Histopathological observations were also in correlation with the biochemical parameters. The activity of ursolic acid (20 mg/kg) compares well with silymarin, a known hepatoprotective drug, and seems to be better in certain parameters. The protective effect of ursolic acid is probably related to its antioxidant activities.
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PMID:Protective effect of ursolic acid on ethanol-mediated experimental liver damage in rats. 1613 16

Hepatic injury elicits intracellular stress that leads to peroxidation of membrane lipids accompanied by alteration of structural and functional characteristics of the membrane, which affects the activity of membrane-bound ATPases. We have explored the effect of leptin on hepatic marker enzyme and membrane-bound adenosine triphosphatases in ethanol-induced liver toxicity in mice. The experimental groups were control, leptin (230 microg kg(-1), i.p. every alternate day for last 15 days), alcohol (6.32 g kg(-1), by intragastric intubation for 45 days), and alcohol plus leptin. Ethanol feeding to mice significantly (P < 0.05) elevated the plasma leptin, alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) and hepatic lipid hydroperoxides (LOOH), and plasma and hepatic total ATPases, Na(+), K(+)-ATPase and Mg(2+)-ATPase. There was a significant decrease in Ca(2+)-ATPase and reduced glutathione (GSH). Leptin injections to ethanol-fed animals further elevated the levels of hepatic LOOH, plasma and hepatic total ATPases, Na(+), K(+)-ATPase and Mg(2+)-ATPase, while the Ca(2)-ATPase and GSH were decreased significantly. In addition, leptin administration was found to increase the plasma levels of leptin, ALT, ALP, GGT, Na(+) and inorganic phosphorous, and decrease the levels of K(+) and Ca(2+) in ethanol-fed mice. These findings were consistent with our histological observations, confirming that leptin enhanced liver ailments in ethanol-supplemented mice.
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PMID:Effect of leptin administration on membrane-bound adenosine triphosphatase activity in ethanol-induced experimental liver toxicity. 1687 59

Individuals affected by liver steatosis seldom have symptoms of liver injury, but may be particularly vulnerable to oxidative insults. In this study, we evaluated liver redox alterations produced by acute ethanol administration to rats that were fed a high-fat diet (HFD). Adult male Wistar rats were fed HFD or standard diet (controls) for 1 month; a group of animals from each condition were gavaged with 35% (vol/vol) ethanol every 12h for the last 3 days of the experiment. Total lipid content determined in liver showed lipid accumulation after HFD or HFD combined with ethanol. HFD alone induced a significant rise of seric alanine aminotransferase levels and a marked reduction of antioxidant enzyme activities (catalase, superoxide dismutase, glutathione transferase). Ethanol alone caused a significant rise of seric cholesterol levels and enhanced mitochondrial H2O2 production, but without apparent oxidative stress as evaluated by thiobarbituric acid-reactive substances (TBARS) assay. The combination of HFD and acute ethanol caused an increase of TBARS, indicating lipid peroxidation, most likely as a consequence of a decrease in antioxidant defenses induced by HFD and of an increase in reactive oxygen species production induced by ethanol. Principal component analysis, based on all the measured parameters, that is, serum liver function tests, antioxidant enzyme activities, mitochondrial H2O2 release, and TBARS, indicated that HFD and ethanol act as two independent factors. In conclusion, our results show that HFD or acute ethanol alone produce, at the most, mild liver injury, whereas their combination triggers oxidative stress, possibly inducing a progression toward liver disease. Hence, our data indicate that a diet too rich in fat is a serious risk factor for the occurrence of liver injury deriving from acute ethanol consumption.
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PMID:Combined effects of high-fat diet and ethanol induce oxidative stress in rat liver. 1741 98

The present study investigates the hepatoprotective effect of fenugreek seed polyphenolic extract (FPEt) against ethanol-induced hepatic injury and apoptosis in rats. Chronic ethanol administration (6 g/kg/day x 60 days) caused liver damage that was manifested by the elevation of markers of liver dysfunction--aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin and gamma-glutamyl transferase (GGT) in plasma and reduction in liver glycogen. The effects on alcohol metabolizing enzymes such as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) were studied and found to be altered in the alcohol-treated group. Ethanol administration resulted in adaptive induction of the activities of cytochrome p450 (cyt-p-450) and cytochrome-b5 (cyt-b5) and reduction in cytochrome-c-reductase (cyt-c-red) and glutathione-S-tranferase (GST), a phase II enzyme. Further, ethanol reduced the viability of isolated hepatocytes (ex vivo) as assessed by the trypan blue exclusion test and increased hepatocyte apoptosis as assessed by propidium iodide staining (PI). Treatment with FPEt restored the levels of markers of liver injury and mitigated the alterations in alcohol metabolizing and detoxification enzymes and the electron transport component cytochrome-c reductase. Increased hepatocyte viability and reduced apoptotic nuclei were observed in FPEt-treated rats. These findings demonstrate that FPEt acts as a protective agent against ethanol-induced abnormalities in the liver. The effects of FPEt are comparable with those of a known hepatoprotective agent, silymarin.
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PMID:Fenugreek (Trigonella foenum graecum) seed polyphenols protect liver from alcohol toxicity: a role on hepatic detoxification system and apoptosis. 1748 88

The alcoholic liver disease usually causes overall immunological alterations which might be attributed to hepatic disease, to ethanol action, and/or to malnourishment. In the present study, efficacy of lecithin with vitamin-B complex to treat ethanol induced immunomodulatory activity was compared with the effect of lecithin alone and tocopheryl acetate (vitamin E). Ethanol (1.6 g/kg body wt/day for 12 weeks) exposure increased thiobarbituric acid reactive substance (TBARS) level, while decreased superoxide dismutase (SOD) activity and reduced glutathione (GSH) content in whole blood hemolysate of 8-10 week-old male BALB/c mice (weighing 20-30 g). The activities of transaminase (AST and ALT) enzymes, interleukin (IL)-10 and gamma interferon (IFN-gamma) elevated, while IL-2 and IL-4 reduced in mice serum due to ethanol exposure. These suggested that oxidative stress and immunomodulatory activities were interdependent and associated with ethanol induced liver damage. Lecithin treatment significantly reduced AST (32.44%), ALT (32.09%), IL-10 (25.63%) activities and TBARS content (12.76%) compared to ethanol treated group. However, lecithin with vitamin-B complex treatment, significantly reduced AST (62.83%); ALT (61.96%); IL-10 (35.88%); IFN-gamma (22.55%) activities and TBARS content (31.58%), while significantly elevated GSH content (36.49%) and SOD activity (61.21%). Tocopheryl acetate treatment significantly reduced AST (62.83%); ALT (61.54%); IL-10 (36.35%): IFN-gamma (23.28%) activities and TBARS content (35.84%). while significantly elevated GSH content (28.76%) and SOD activity (62.42%) compared to ethanol treated group. These findings persuasively argued that lecithin with vitamin-B complex was a new promising therapeutic approach in controlling ethanol induced immunomodulatory activities involving liver damage processes. Prevention of oxidative stress with correction of nutritional deficiency caused alteration in the ethanol-induced immunomodulatory activities and associated liver diseases.
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PMID:Effect of lecithin with vitamin-B complex and tocopheryl acetate on long-term effect of ethanol induced immunomodulatory activities. 1787 44

Hepatocyte retinoid X receptor alpha (RXRalpha)-deficient mice are more sensitive to ethanol toxicity than wild-type mice. Because RXRalpha-mediated pathways are implicated in lipid homeostasis and the inflammatory response, we hypothesized that a compromise in lipid metabolism and associated production of proinflammatory mediators are responsible for the hepatotoxicity observed in ethanol-treated hepatocyte RXRalpha-deficient mice. Wild-type and hepatocyte RXRalpha-deficient mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks. After ethanol treatment, serum ALT levels increased significantly (4-fold) in hepatocyte RXRalpha-deficient mice, but not in the wild-type mice. Hepatic liver fatty acid binding protein (L-FABP) mRNA and protein levels were reduced due to RXRalpha deficiency. Ethanol induced L-FABP mRNA and protein in wild-type mice and provided protection against nonesterified fatty acid toxicity; however, this effect was absent in the mutant mice. Accordingly, hepatic nonesterified fatty acid level was increased in ethanol-fed mutant mice. Ethanol increased nuclear factor (NF)-kappaB binding activity in hepatocyte RXRalpha-deficient mice, but not in wild-type mice. In agreement, hepatic mRNA levels of proinflammatory cytokines and chemokines were increased to a greater extent in the mutant than in wild-type mice. Furthermore, signal transducer and activator of transcription factor (STAT) 3 and associated Bcl-xL induction was observed in ethanol-fed wild-type mice but not in ethanol-fed hepatocyte RXRalpha-deficient mice. Taken together, after ethanol treatment, hepatocyte RXRalpha deficiency results in lack of L-FABP induction, increased hepatic free fatty acids, NF-kappaB activation, and proinflammatory cytokines production and a lack of STAT3 activation, which in part may contribute to alcohol-induced liver damage.
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PMID:Hepatocyte retinoid X receptor alpha-dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol-induced liver injury. 1797 11

The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (six/group) received one of four Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined. Both MCD and ethanol induced macrovesicular steatosis. However, the combination diet produced massive steatosis with minor necrosis and inflammation. MCD and combination diets, but not ethanol, induced serum ALT levels by 1.6- and 10-fold, respectively. MCD diet, but not ethanol, also induced serum alkaline phosphatase levels suggesting bile duct injury. Ethanol increased liver fatty acid binding protein (L-FABP) mRNA and protein levels. In contrast, the combination diet decreased L-FABP mRNA and protein levels and increased hepatic free fatty acid and lipid peroxide levels. Ethanol, but not MCD, reduced hepatic S-adenosylmethionine (SAM) and GSH levels. Hepatic TNFalpha protein levels were increased in all treatment groups, however, IL-6, a hepatoprotective cytokine which promotes liver regeneration was increased in ethanol-fed mice (2-fold), but decreased in the combination diet-treated mice. In addition, the combination diet reduced phosphorylated STAT3 and Bcl-2 levels. While MCD diet might cause bile duct injury and cholestasis, ethanol preferentially interferes with the SAM-GSH oxidative stress pathway. The exacerbated liver injury induced by the combination diet might be explained by reduced L-FABP, increased free fatty acids, oxidative stress, and decreased IL-6 protein levels. The combination diet is an efficient model of steatohepatitis.
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PMID:The pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury. 1803 73

This study was designed to determine whether dietary epigallocatechin-3-gallate (EGCG), the most abundant catechin polyphenol in green tea, can protect the liver from cytochrome P450 2E1 (CYP2E1)-dependent alcoholic liver damage. Compared with an ethanol group, when EGCG was present in the ethanol diet, the formation of a fatty liver was significantly reduced and the serum aspartate transaminase (AST) and alanine transaminase (ALT) levels were much lower. Ethanol treatment significantly elevated hepatic CYP2E1 expression while simultaneously reducing hepatic phospho-acetyl CoA carboxylase (p-ACC) and carnitine palmitoyl-transferase 1 (CPT-1) levels. While EGCG markedly reversed the effect of ethanol on hepatic p-ACC and CPT-1 levels, it had no effect on the ethanol-induced elevation in CYP2E1 expression. EGCG prevents ethanol-induced hepatotoxicity and inhibits the development of a fatty liver. These effects were associated with improvements in p-ACC and CPT-1 levels. The use of EGCG might be useful in treating patients with an alcoholic fatty liver.
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PMID:Effect of dietary epigallocatechin-3-gallate on cytochrome P450 2E1-dependent alcoholic liver damage: enhancement of fatty acid oxidation. 1807 Dec 71


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