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)

Carbon tetrachloride (CCl(4)) is a known hepatotoxic compound working through the generation of reactive free radicals. Selenium (Se) is an essential trace element required by animals and humans for protection against xenobiotic compounds. In this study, Se, as diphenylmethyl selenocyanate, has been evaluated for its protective action against CCl(4)-induced hepatotoxicity in Swiss albino mice. Treatment with Se compound was found to upregulate different phase II detoxifying enzymes (catalase, superoxide dismutases, reduced glutathione, and glutathione transferase) in liver of mice challenged with different doses of CCl(4) as compared to the CCl(4) control, when measured after 24 hours of CCl(4) treatment (p < 0.01). The Se compound also significantly (p < 0.01) inhibited the level of membrane lipid peroxidation and serum transferase activity (ALT and AST) in the treated group as compared to the control group.
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PMID:Protective effect of diphenylmethyl selenocyanate against carbon tetrachloride-induced hepatotoxicity in vivo. 1551 Dec 16

Total parenteral nutrition (TPN) is associated with cholestasis and hepatic steatosis in human infants. The present study focused on the changes in hepatic xenobiotic transporters associated with overdose of fat-free or fat-containing TPN in infant rats. Three-week-old male Sprague-Dawley rats were divided into three groups: group 1 received an oral diet, group 2 received TPN without fat, and group 3 received TPN with 20% of its calories from fat (soybean oil emulsion). After TPN administration for 4 days, both serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, which are indicators of hepatic dysfunction, in group 2 were significantly higher (p<0.001) than those in the other groups, whereas there were no differences between groups 1 and 3 in either serum AST or ALT levels. The serum bilirubin concentration in group 2 was also markedly higher than that in the other groups. Mdr2, Bsep, Mrp2, Mrp6, Oct1, and Oat2 mRNA levels were decreased in group 2 (fat-free TPN) compared with those in group 1 (oral diet), whereas Mdr1b, Mrp1, and Mrp5 mRNA levels were increased. Specifically, the level of Mdr1b mRNA in group 2 was 16 times higher (p<0.001) than that in group 1. On the other hand, the changes in these mRNA expression levels in group 3 (fat-containing TPN) were smaller than those in group 2, and specifically, the expression levels of Mdr1b, Mrp1, Mrp5, Mrp6, and Oat2 mRNA in group 3 were not significantly different from those in group 1. The results of the present study indicate that including fat in the TPN regimen is very important in preventing the mRNA up- and down-regulation of xenobiotic transporters, which is considered to be the main factor responsible for the abnormal hepatic changes such as cholestasis associated with the excessive administration of fat-free TPN.
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PMID:Role of soybean oil fat emulsion in the prevention of hepatic xenobiotic transporter mRNA up- and down-regulation induced by overdose of fat-free total parenteral nutrition in infant rats. 1577 74

4,4'-Methylenedianiline (MDA) is widely used in the manufacturing of polyurethane foam, epoxy resins, and polymers. Exposure to MDA induces liver damage in humans and rats. MDA undergoes N-acetylation catalyzed by N-acetyltransferase 1 (NAT1) and 2 (NAT2) in the liver. Both human and rat NAT2 are polymorphic, and human NAT2 genetic polymorphism modifies the frequency and/or severity of drug and xenobiotic toxicity in human populations. Recombinant expression of rat Nats in Escherichia coli showed that MDA was acetylated by both recombinant rat Nat1 and Nat2 and was catalyzed at substantially higher rates by rapid acetylator Nat2 compared with slow acetylator Nat2. Rapid acetylator F344 rat liver cytosols catalyzed the N-acetylation of MDA at significantly higher rates than those from slow acetylator Wistar-Kyoto (WKY) inbred rats. To test the effect of NAT2 genetic polymorphism on hepatotoxicity from acute MDA exposure, we compared hepatotoxicity in rapid (F344) and slow (WKY) Nat2 acetylator inbred rats that were administered MDA. Based on the results of dose-response studies ranging up to 150 mg/kg MDA administered by intragastric gavage, the effect of a moderately hepatotoxic dose (37.5 mg/kg) was compared in rapid versus slow acetylator rats. Plasma alanine transaminase enzyme activities were approximately 5-fold higher (p < 0.05) in rapid versus slow acetylator rats after MDA treatment, and necrotizing hepatitis with portal damage consisting of bile ductular necrosis, portal expansion, and inflammation was clearly more prominent. These results suggest that acetylator phenotype is an important factor for susceptibility toward MDA hepatotoxicity.
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PMID:4,4'-methylenedianiline-induced hepatotoxicity is modified by N-acetyltransferase 2 (NAT2) acetylator polymorphism in the rat. 1619 14

The liver plays an important role in the modulation of the process of carcinogenesis, as it is the primary site for the biotransformation of xenobiotics including carcinogens as well as anticancer drugs. The present study was designed to evaluate the biochemical alterations occurring in the liver of 7,12-dimethylbenz(a)anthracene (DMBA) induced skin tumor bearing male Balb/c mice and their modulation by aqueous Azadirachta indica leaf extract (AAILE). It was observed that skin tumor induction caused hepatic damage characterized by a decreased hepatosomatic index and significantly increased (p < 0.001) activities of the hepatic tissue injury marker enzymes, namely alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase. However, upon treatment with AAILE, the above-mentioned alterations, including the increased activities of hepatic tissue injury marker enzymes, were significantly reversed, which signified the hepato-protective efficacy of Azadirachta indica. Increased oxidative stress was also observed in the hepatic tissue of skin tumor bearing mice as revealed by a significant increase (p < 0.001) in lipid peroxidation levels and a decrease in reduced glutathione contents and activities of various antioxidant enzymes studied, namely glutathione-S-transferase, glutathione peroxidase and glutathione reductase. The AAILE treatment reduced oxidative stress by decreasing lipid peroxidation levels and enhancing the reduced glutathione contents and activities of various antioxidant enzymes. The activities of the xenobiotic biotransformation enzymes, namely cytochrome P450, cytochrome b5 and glutathione-S-transferase, were found to be decreased in the hepatic tissue of tumor bearing mice. Treatment with AAILE further caused a decrease in the activity of cytochrome P450 and cytochrome b5, whereas it up-regulated the activity of glutathione-S-transferase. The significance of these observations with respect to the progress of the process of carcinogenesis is explained in the present research article.
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PMID:Chemomodulatory effects of Azadirachta indica on the hepatic status of skin tumor bearing mice. 1652 Nov 6

We tested the hypothesis that environmental stress is a predisposing factor for liver injury by examining the effect of acute restraint on liver injury provoked by carbon tetrachloride (CCl4) and allyl alcohol. Mice were immobilized using Plexiglas restraint cages, producing a form of psychogenic stress, whereas other animals were allowed to roam free. Serum alanine aminotransferase levels were elevated significantly in restrained animals after administration of varying doses of CCl4 or allyl alcohol that did not produce liver injury in unrestrained animals. This enhanced liver injury after CCl4 was seen in both male and female mice. The duration of acute restraint was found to be important because a period of 2.5 h of restraint enhanced hepatotoxicity, whereas shorter periods of restraint did not significantly increase liver injury. Serum corticosterone concentrations increased, whereas hepatic glutathione content decreased during and after acute restraint. In addition, delay in administration of CCl4 until 5 h after completion of restraint also produced an elevated level of liver injury compared with that seen in free roaming animals. Immunohistochemical examination of the livers showed significantly enhanced Kupffer cell activation in restrained mice compared with that of free roaming mice. These observations suggest that induction of psychogenic stress may increase the susceptibility to liver injury observed with classic hepatotoxicants and may represent an important predisposing factor to liver injury after xenobiotic exposure. The underlying mechanism seems to be increased macrophage activation in the liver, which may subsequently sensitize hepatocytes to xenobiotics and thus enhance hepatotoxicity.
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PMID:Enhanced xenobiotic-induced hepatotoxicity and Kupffer cell activation by restraint-induced stress. 1656 54

Propolis, a natural beehive product has been known for centuries for a variety of beneficial traditional medicinal properties. The present study was conducted to ascertain the antineoplastic potential of propolis along with paclitaxel against experimental mammary carcinogenesis. Female Sprague Dawley rats at 55 days of age were treated with dimethylbenz(a)anthracene to induce breast cancer. Paclitaxel at a dose of 33 mg/kg body mass intraperitoneally and propolis 50 mg/kg body weight orally was administered to the experimental animals, immediately after the carcinogen treatment and continued until the termination of the study. At the end of the treatment activities of phase I and II xenobiotic metabolizing enzymes and liver marker enzymes were measured. A significant increase in carcinogen activating enzymes, cytochrome P(450), cytochrome b(5) and NADPH cytochrome C reductase with concomitant decrease in phase II enzymes, glutathione transferase and UDP-glucuronyl transferase were observed in animals with mammary cancer. Furthermore there was a significant decrease in alanine aminotransferase, aspartate aminotransferase with a sharp increase in alkaline phosphatase, acid phosphatase and 5' nucleotidase. Propolis treatment caused the activity of these enzymes return to almost normal control levels, indicating the protective effect of propolis against dimethyl benz(a) anthracene induced carcinogenesis. On the basis of the observed results propolis can be considered a promising chemotherapeutic agent and can be administered as an adjuvant with paclitaxel chemotherapy.
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PMID:Therapeutic effect of propolis and paclitaxel on hepatic phase I and II enzymes and marker enzymes in dimethylbenz(a)anthracene-induced breast cancer in female rats. 1672 Jan 5

The effect of exposure to sublethal concentrations (0.017 mg L(-1), 1/10 of LC50) of the novel organophosphate (OP) insecticide, 2-butenoic acid-3-(diethoxyphosphinothioyl) methyl ester (RPR-II) on biochemical parameters in Oreochromis mossambicus was studied during exposure for 3, 7, 15, 30 and its recovery response after seven days. Acetylcholinesterase (AChE) activity of brain, gill and muscle was inhibited by 67%, 77% and 73% respectively on day-30. The plasma and kidney alanine aminotransferase (AlaAT), and aspartate aminotransferase (AspAT) activity increased, while decreases were observed in gill and liver. Increases in acid phosphatase (AcP), and alkaline phosphatase (AP) activities were observed in plasma, gill, and kidney, and reductions of 20% and 61% in liver AcP and AP, respectively. Depletion of glycogen was observed in all tissues, an indication of typical stress related response of the fish with pesticide. Lactate dehydrogenase (LDH) activity decreased in liver and muscle, indicating tissue damage but a significant increase in LDH activity in gill and brain was observed. Depletion of glutathione (GSH) was observed in all tissues, thereby enhancing lipid peroxidation resulting in cell damage. The induction in hepatic glutathione-S-transferase (GST) levels indicates protection against the toxicity of xenobiotic-induced lipid peroxidation. There was a significant recovery in the above biochemical parameters, in all tissues of fish after a recovery period of seven days. These results revealed that the OP insecticide RPR-II is highly toxic and affects the intermediary metabolism of O. mossambicus.
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PMID:Sublethal effects of an organophosphorus insecticide (RPR-II) on biochemical parameters of tilapia, Oreochromis mossambicus. 1676 96

Previous study using Cyp2e1-null mice showed that Cyp2e1 is required in CCl(4)-induced liver injury at 24h, what remains unclear are the temporal changes in liver damage and the spectrum of genes involved in this process. We investigated the time-dependent liver changes that occurred at morphological, histopathological, biochemical and molecular levels in both Cyp2e1(+/+) and Cyp2e1(-/-) mice after treating with either corn oil or CCl(4) (1 ml/kg) for 2, 6, 12, 24 and 48 h. A pale orange colored liver, indicative of fatty infiltration, was observed in Cyp2e1(+/+) mice treated with CCl(4) for 24 and 48 h, while the Cyp2e1(+/+) mice treated with corn oil and Cyp2e1(-/-) mice treated with either corn oil or CCl(4) showed normal reddish brown colored liver. Ballooned hepatocytes with multiple vacuoles in their cytoplasm were observed in the livers of Cyp2e1(+/+) mice 24 and 48 h after treating with CCl(4). The levels of serum alanine aminotransferase and aspartate aminotransferase, markers for liver injury, were significantly higher at 12h, peaked at 24h and gradually decreased at 48 h after CCl(4) intoxication. In contrast, this kind of damage was not apparent in the Cyp2e1(-/-) mice treated with CCl(4). Altered expressions of genes related to liver cirrhosis, apoptosis, oxidative stress, xenobiotic detoxification, lipid metabolism, chemsensory signaling or tumorigenesis, structural organization, regeneration and inflammatory response were identified, and the time-dependent changes in expression of these genes were varied. Overall, the present study provides insights into the mechanism of CCl(4)-induced hepatotoxicity in animal models.
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PMID:A temporal study on the histopathological, biochemical and molecular responses of CCl(4)-induced hepatotoxicity in Cyp2e1-null mice. 1708 9

There are currently no accurate and well-validated short-term tests to identify nongenotoxic hepatic tumorigens, thus necessitating an expensive 2-year rodent bioassay before a risk assessment can begin. Using hepatic gene expression data from rats treated for 5 days with one of 100 structurally and mechanistically diverse nongenotoxic hepatocarcinogens and nonhepatocarcinogens, a novel multigenebiomarker (i.e., signature) was derived to predict the likelihood of nongenotoxic chemicals to induce liver tumors in longer term studies. Independent validation of the signature on 47 test chemicals indicates an assay sensitivity and specificity of 86% and 81%, respectively. Alternate short-term in vivo pathological and genomic biomarkers were evaluated in parallel for comparison, including liver weight, hepatocellular hypertrophy, hepatic necrosis, serum alanine aminotransferase activity, induction of cytochrome P450 genes, and repression of Tsc-22 or alpha2-macroglobulin messenger RNA. In contrast to these biomarkers, the gene expression-based signature was more accurate. Unlike existing tests, an understanding of potential modes of action for hepatic tumorigenicity can be derived by comparison of the signature profile of test chemicals to hepatic tumorigens of known mechanism, including regenerative proliferation, proliferation associated with xenobiotic receptor activation, peroxisome proliferation, and steroid hormone-mediated mechanisms. This signature is not only more accurate than current methods, but also facilitates the identification of mode of action to aid in the early assessment of human cancer risk.
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PMID:A gene expression biomarker provides early prediction and mechanistic assessment of hepatic tumor induction by nongenotoxic chemicals. 1755 6

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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