Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin (CDDP) is a widely used anticancer drug, but at high dose, it can produce undesirable side effects such as hepatotoxicity. Because silymrin has been used to treat liver disorders, the protective effect of silymarin on CDDP-induced hepatotoxicity was evaluated in rats. Hepatotoxicity was determined by changes in serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST], nitric oxide [NO] levels, albumin and calcium levels, and superoxide dismutase [SOD], glutathione peroxidase [GSHPx] activities, glutathione content, malondialdehyde [MDA] and nitric oxide [NO] levels in liver tissue of rats. Male albino rats were divided into four groups, 10 rats in each. In the control group, rats were injected i.p. with 0.2 ml of propylene glycol in saline 75/25 (v/v) for 5 consecutive days [Silymarin was dissolved in 0.2 ml of propylene glycol in saline 75/25 v/v]. The second group were injected with CDDP (7.5 mg /kg, I.P.), whereas animals in the third group were i.p. injected with silymarin at a dose of 100 mg/kg/day for 5 consecutive days. The Fourth group received a daily i.p. injection of silymarin (100 mg/kg/day for 5 days) 1 hr before a single i.p. injection of CDDP (7.5 mg/kg). CDDP hepatotoxicity was manifested biochemically by an increase in serum ALT and AST, elevation of MDA and NO in liver tissues as well as a decrease in GSH and the activities of antioxidant enzymes, including SOD, GSHPx in liver tissues. In addition, marked decrease in serum NO, albumin and calcium levels were observed. Serum ALT, AST, liver NO level, MDA was found to decreased in the combination group in comparison with the CDDP group. The activities of SOD, GSHPx, GSH and serum NO were lower in CDDP group than both the control and CDDP pretreated with silymarin groups. The results obtained suggested that silymarin significantly attenuated the hepatotoxicity as an indirect target of CDDP in an animal model of CDDP-induced nephrotoxicity.
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PMID:Silymarin modulates Cisplatin-induced oxidative stress and hepatotoxicity in rats. 1712 99

Alcoholic liver disease (ALD) is one of the most common diseases in society. A large number of studies are in progress to identify natural substances that are effective in reducing the severity of ALD. 2-Hydroxy-4-methoxy benzoic acid (HMBA), the active principle of Hemidesmus indicus, an indigenous Ayurvedic medicinal plant in India, is expected to significantly inhibit the development of liver injury in ethanol administration. It is expected to reduce the severity of liver damage in terms of body weight, hepatic marker enzymes, oxidative stress, antioxidant status and histological changes in ethanol-induced hepatotoxic rats. Hepatotoxicity was induced by administering 20% ethanol (5 g kg(-1) daily) for 60 days to male Wistar rats, which resulted in significantly decreased body weight and an increase in liver-body weight ratio. The liver marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, gamma-glutamyl transpeptidase and lactate dehydrogenase were elevated. In addition, the levels of plasma, erythrocyte and hepatic thiobarbituric acid reactive substances, hydroperoxides and conjugated dienes were also elevated in ethanol-fed rats as compared with those of the experimental control rats. Decreased activity of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, vitamin C and alpha-tocopherol was also observed on alcohol administration as compared with experimental control rats. HMBA was co-administered at a dose of 200 mug kg(-1) daily for the last 30 days of the experiment to rats with alcohol-induced liver injury, which significantly increased body weight, significantly decreased the liver-body weight ratio, transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and lactate dehydrogenase, significantly decreased the levels of lipid peroxidative markers, significantly elevated the activity of enzymic and non-enzymic antioxidants in plasma, erythrocytes and liver and also increased levels of plasma and liver vitamin C and alpha-tocopherol at the end of the experimental period as compared with untreated ethanol-administered rats. The histological changes were also in correlation with the biochemical findings. The results suggest that HMBA administration may afford protection against ethanol-induced liver injury in rats.
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PMID:Antioxidant effect of 2-hydroxy-4-methoxy benzoic acid on ethanol-induced hepatotoxicity in rats. 1733 49

In this study, we investigated the safety and toxicity of isoniazid (INH) intervention therapy to the patients with latent tuberculosis who were given tumor necrosis factor alpha (TNFalpha) for the treatment of their rheumatologic diseases. In this prospective clinical study, we enrolled 86 patients receiving anti-TNFalpha therapy for their rheumatologic diseases between April 2005 and September 2006. Of all the subjects, 45 had rheumatoid arthritis, 36 had ankylosing spondylitis, and 5 had psoriatic arthritis. In addition to anti-TNFalpha therapy, 60 of the 86 patients were given INH intervention for revealed latent tuberculosis. INH at a dosage of 300 mg daily was given for 9 months. Hepatotoxicity due to the INH therapy was considered when the serum alanine aminotransferase (ALT) and/or aspartate aminotransaminase (AST) levels showed at least threefold increase with respect to their baseline serum levels. Serum ALT and AST levels were measured by enzymatic colorimetric method in fasting peripheral blood samples at 0 (baseline), 1, 2, 3, 6, and 9 months. Of 86 patients, 47 (54.7%) were women (mean age+/-SD, 44.1 +/- 10.9 years) and 39 (45.3%) were men (38.8 +/- 10.1 years). Except five patients (8.3%), liver toxicity due to the INH therapy was not encountered among the patients, and after temporarily discontinuing the INH therapy of these five subjects, serum transaminase levels returned to the normal ranges. No hepatotoxicity was observed in the non-INH group. However, there was no statistical significance between INH-treated and non-INH-treated group (p = 0.317). In addition, none of the 86 patients developed active tuberculosis infection during the treatment period. In conclusion, for those patients who were assigned to the TNFalpha treatment for their rheumatologic disorders and carrying risk for latent tuberculosis, INH intervention therapy was found to be safe and efficacious.
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PMID:Isoniazid intervention for latent tuberculosis among 86 patients with rheumatologic disease administered with anti-TNFalpha. 1733 73

Cisplatin is a potent and widely used chemotherapeutic agent. Nephrotoxicity induced by this drug has been well documented. However, very little information is available on cisplatin-induced hepatotoxicity and its underlying mechanism remains unclear. High doses of cisplatin have been known to produce hepatotoxicity. Additionally, elevated expression of CYP 2E1 has been associated with enhanced cisplatin-induced hepatotoxicity. Several studies suggest that cisplatin toxicity occurs by the increased generation of reactive oxygen species (ROS) in mitochondria. Therefore, the present study examined, in vivo, the cisplatin-induced effects on hepatic mitochondrial structure and function as well as the occurrence of hepatocellular death by apoptosis. Adult male Wistar rats (200-220 g) were divided into two groups (n=8) treated as follows: (1) control group (saline solution, 1 ml 100 g(-1) body weight, i.p.) and (2) cisplatin group (10 mg kg(-1) body weight, i.p.). The animals were killed 72 h after the treatment. Hepatotoxicity was evidenced in the cisplatin group by the increased serum levels of alanine (ALT) and aspartate (AST) aminotransferases. The mechanism of cisplatin-induced hepatotoxicity was found to involve membrane rigidification; decreased GSH/GSSG ratio, ATP, GSH and NADPH levels; lipid peroxidation; oxidative damage of cardiolipin and protein sulfhydryl groups. Moreover, cell death by apoptosis was also demonstrated and the findings strongly suggest the participation of the mitochondrial signaling pathway in this process. Therefore, the results show the key role of mitochondria in the hepatotoxicity induced by cisplatin and delineate several mitochondrial processes that could be targeted in future cytoprotective therapy approaches.
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PMID:Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. 1760 43

Oxidative damage is implicated in the pathogenesis of various liver injuries. In the present study the ability of Pycnogenol (PYC) as an antioxidant to protect against CCl4-induced oxidative stress and hepatotoxicity in rats was investigated. Four experimental groups of six rats each were constructed: a vehicle control group received the respective vehicles (distilled water and corn oil) only; a CCl4 group received a 14-day repeated intraperitoneal (i.p.) dose of distilled water and then a single oral dose of CCl4 at 1.25 ml/kg; and the CCl4&PYC 10 and CCl4&PYC 20 groups received a 14-day repeated i.p. dose of PYC 10 and 20 mg/kg, respectively, and then a single oral dose of CCl4 at 1.25 ml/kg. Hepatotoxicity was assessed 24 h after the CCl4 treatment by measurement of serum aminotransferase (AST) and alanine aminotransferase (ALT) activities, hepatic malondialdehyde (MDA) and glutathione (GSH) concentrations, and catalase, superoxide dismutase (SOD), and glutathione-S-transferase (GST) activities. The results were confirmed histopathologically. The single oral dose of CCl4 produced significantly elevated levels of serum AST and ALT activities. Histopathological examinations showed extensive liver injuries, characterized by extensive hepatocellular degeneration/necrosis, fatty changes, inflammatory cell infiltration, congestion, and sinusoidal dilatation. In addition, an increased MDA concentration and decreased GSH, catalase, SOD, and GST were observed in the hepatic tissues. On the contrary, PYC treatment prior to the administration of CCl4 significantly prevented the CCl4-induced hepatotoxicity, including the elevation of serum AST and ALT activities and histopathological hepatic lesions, in a dose-dependent manner. Moreover, MDA and GSH levels and catalase, SOD, and GST activities in hepatic tissues were not affected by administration of CCl4, indicating that the pretreatment of PYC efficiently protects against CCl4-induced oxidative damage in rats. The results indicate that PYC has a protective effect against acute hepatotoxicity induced by the administration of CCl4 in rats, and that the hepatoprotective effects of PYC may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity.
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PMID:Protective effects of Pycnogenol on carbon tetrachloride-induced hepatotoxicity in Sprague-Dawley rats. 1790 Jul 80

Furfuryl alcohol (FA) and 2-furyl methyl ketone (2FMK) are two dietary furans with wide industrial applications and also found in a variety of food items. In a mouse test system, the mutagenicity of these two compounds after five days of exposure has been reported. In the present study histopathological changes and biochemical alterations after a period of 5-90 days of exposure have been evaluated in target organs like liver and kidney. Hepatotoxicity in the form of pycnosis, vacuolation and focal necrosis was observed after 60 and 90 days of treatment with 2000 and 4000 ppm of FA. Kidney showed damage to tubular epithelium only after treatment with 4000 ppm of FA. 2-FMK did not show any noticeable damage to liver or kidney. Significant variations in total protein content and activity of aspartate and alanine aminotransferase (ASAT and ALAT) were observed in both liver and kidney after longer exposure to both the furans. There was an increased expression of two proteins of 92 and 94 KD in the liver of treated animals irrespective of the concentration or duration. It is apparent from the present study that dietary contamination with furans has definite hepatic and renal toxicity potentials in man.
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PMID:Monitoring cytotoxic potentials of furfuryl alcohol and 2-furyl methyl ketone in mice. 1790 64

The clinical utility of cyclophosphamide (CYP) as an anticancer drug is limited by its urotoxicity and nephrotoxicity and to a lesser extent by its hepatotoxicity. The present study was undertaken in order to find out the reason why liver is least susceptible of the three organs to CYP-induced damage although it is the major site for drug activation and metabolism. Adult female Wistar rats weighing 200-250 g were administered single intraperitoneal injection of CYP at the dose of 150 mg/kg body weight and sacrificed at various time intervals 6, 16 or 24h after the dose of CYP. The control rats were administered saline alone. Hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) activity and histopathology of the liver. Liver was used for the assay of reduced glutathione; activity of paraoxonase (PON1) malondialdehyde - marker of lipid peroxidation. Serum was used for the assay of ALT activity and PON1 activity. The level of reduced glutathione in the liver CYP treated rat was increased by 22% and 57% at 16 and 24h, respectively. Interestingly, a marked increase in the activity of PON1 (122%) was observed in the livers of CYP treated rats 24h after treatment. This was accompanied by significant increase in PON1 activity (23%) in the serum. No significant alteration in hepatic malondialdehyde level was observed at any time period after treatment. Serum ALT activity was increased slightly 24h after treatment with CYP. Mild liver damage was observed histologically only 24h after treatment with the drug. The present investigation shows for the first time that an increase in antioxidant levels in the liver may be a defense mechanism to prevent/minimize CYP-induced liver damage.
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PMID:Increased glutathione levels and activity of PON1 (phenyl acetate esterase) in the liver of rats after a single dose of cyclophosphamide: a defense mechanism? 1803

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

In the clinical setting, antidotes are generally administered after the occurrence of a drug overdose. Therefore, the most pertinent evaluation of any new agent should model human exposure. This study tested whether acetaminophen (APAP) hepatotoxicity was reversed when S-adenosyl-L-methionine (SAMe) was administered after APAP exposure, similar to what occurs in clinical situations. Comparisons were made for potency between SAMe and N-acetylcysteine (NAC), the current treatment for APAP toxicity. Male C57BL/6 mice were fasted overnight and divided into groups: control (VEH), SAMe treated (SAMe), APAP treated (APAP), N-acetylcysteine treated (NAC), SAMe or NAC administered 1h after APAP (SAMe+APAP) and (NAC+APAP), respectively. Mice were injected intraperitoneal (i.p.) with water (VEH) or 250 mg/kg APAP (15 ml/kg). One hour later, mice were injected (i.p.) with 1.25 mmol/kg SAMe (SAMe+APAP) or NAC (NAC+APAP). Hepatotoxicity was evaluated 4h after APAP or VEH treatment. APAP induced centrilobular necrosis, increased liver weight and alanine transaminase (ALT) levels, depressed total hepatic glutathione (GSH), increased protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins. Treatment with SAMe 1h after APAP overdose (SAMe+APAP) was hepatoprotective and was comparable to NAC+APAP. Treatment with SAMe or NAC 1h after APAP was sufficient to return total hepatic glutathione (GSH) to levels comparable to the VEH group. Western blot showed reversal of APAP mediated effects in the SAMe+APAP and NAC+APAP groups. In summary, SAMe was protective when given 1h after APAP and was comparable to NAC.
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PMID:Comparison of S-adenosyl-L-methionine (SAMe) and N-acetylcysteine (NAC) protective effects on hepatic damage when administered after acetaminophen overdose. 1806 90

Antitubercular drug induced hepatotoxicity is a major hurdle for an effective treatment of tuberculosis. The present study was undertaken to assess the hepatoprotective potential of tocopherol (50 mg/kg and 100 mg/kg, ip) and to compare it with cimetidine (120 mg/kg, ip). Hepatotoxicity was produced by giving isoniazid (INH, 50 mg/kg, po) and rifampicin (RMP, 100 mg/kg, po) combination to albino rabbits for 7 days. Assessment of liver injury was done by estimating levels of alanine transaminase (ALT) and argininosuccinic acid lyase (ASAL) in serum and by histopathological examination of liver. Results revealed that pretreatment with high dose of tocopherol (100 mg/kg) prevented both biochemical as well as histopathological evidence of hepatic damage induced by INH and RMP combination. Moreover, tocopherol (100 mg/kg) was found to be a more effective hepatoprotective agent as compared to cimetidine.
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PMID:Hepatoprotective effect of tocopherol against isoniazid and rifampicin induced hepatotoxicity in albino rabbits. 1825 8


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