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)

The susceptibility to lipid peroxidation (LPO) of liver, kidneys, brains, lungs, heart, and testes was assessed in rats administered intraperitoneally with various doses of cadmium (Cd). Dose-response studies were carried out with male Long Evans rats (12-week-old; 300 +/- 33 g) injected with 25, 125, 500, and 1250 micrograms Cd/kg as CdCl2 and sacrificed after 24 h. In time-response studies, animals were administered with 25 and 500 micrograms Cd/kg as CdCl2 and sacrificed after 2, 6, 12, 24, and 72 h. Exposure of rats to low and moderate doses of Cd by the intraperitoneal route stimulated LPO in all the tissues investigated as assessed by the measurement of thiobarbituric acid reactive substances (TBARS). Lungs and brain were the most responsive, and these tissues and liver displayed early responses following Cd exposure. Comparison of LPO to various tissue indicators (for liver: alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), alkaline phosphatase (ALP); for lungs: ALP, gamma-glutamyl transpeptidase (GGT] suggested that low doses of Cd stimulated LPO without any evidence of acute damages. These results suggest that LPO is an early and sensitive consequence of Cd exposure as determined in various organs. Investigation of liver, lungs, and heart antioxidant defense system components (glutathione peroxidase (GPX), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), superoxide dismutase (SOD] revealed that GPX might be considered as a potential modulator of the Cd-induced LPO reaction in lungs and heart tissues.
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PMID:Studies on lipid peroxidation in rat tissues following administration of low and moderate doses of cadmium chloride. 182 34

Antimony potassium tartrate (APT) is a complex salt that until recently was used worldwide as an antischistosomal drug. Treatment was efficacious only if APT was administered intravenously to humans at a near lethal total dose of 36 mg/kg. Because unconfirmed epidemiologic studies suggested there might be an association between APT treatment and bladder cancer, we initiated prechronic toxicity studies with the drug to select a route of administration and doses in the event that chronic studies of APT were needed. The toxicity and concentration of tissue antimony levels were compared in 14-d studies with F344 rats and B6C3F1 mice administered APT in the drinking water or by ip injection to determine the most appropriate route for longer term studies. Drinking water doses estimated by water consumption were 0, 16, 28, 59, 94 and 168 mg/kg in rats and 0, 59, 98, 174, 273, and 407 mg/kg in mice. APT was poorly absorbed and relatively nontoxic orally, whereas ip administration of the drug caused mortality, body weight decrements, and lesions in the liver and kidney at doses about one order of magnitude below those in drinking water. Because of these data and the dose-related accumulation of antimony in the target organs, an ip dose regimen was selected for subsequent studies. Both sexes of F344 rats and B6C3F1 mice were given 0, 1.5, 3, 6, 12, and 24 mg/kg doses of APT every other day for 90 d by ip injection. There were no clinical signs of toxicity nor gross or microscopic lesions in mice that could be attributed to toxicity of APT, although elevated concentrations of antimony were detected in the liver and spleen of mice. Rats were more sensitive than mice to the toxic effects of APT, exhibiting dose-related mortality, body weight decrements, and hepatotoxicity. The concentrations of antimony measured in liver, blood, kidney, spleen, and heart of rats were proportional to dose, but there were no biochemical changes indicative of toxicity except in the liver. Hepatocellular degeneration and necrosis occurred in association with dose-related elevations in activities of the liver-specific serum enzymes sorbitol dehydrogenase and alanine aminotransferase. By alternating the site of abdominal injection and the days of treatment, mesenteric inflammation at the site of administration was minimized in the rats and mice, indicating that the ip route would be suitable for chronic studies.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Comparative toxicity and tissue distribution of antimony potassium tartrate in rats and mice dosed by drinking water or intraperitoneal injection. 189 Jun 93

Piperine, a major pungent constituent of black and red peppers, was administered to rats intragastrically and intraperitoneally to study whether it alters the activities of hepatic mixed-function oxidases (MFO) and serum enzymes as specific markers of hepatotoxicity. An intragastric dose of 100 mg/kg of piperine to adult, male Sprague-Dawley rats caused an increase in hepatic microsomal cytochrome P-450 and cytochrome b5, NADPH-cytochrome c reductase, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h following treatment. On the other hand, a 10 mg/kg dose given i.p. exhibited no effect on the activities of the aforementioned parameters of the hepatic drug-metabolizing enzyme system. However, when the intragastric and intraperitoneal doses were increased to 800 mg/kg and 100 mg/kg, respectively, the black pepper alkaloid produced a significant decrease in the levels of cytochrome P-450, benzphetamine N-demethylase, aminopyrine N-demethylase and aniline hydroxylase 24 h after treatment. None of the treatments significantly elevated the activities of serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and isocitrate dehydrogenase (ICD), suggesting that piperine is not a hepatotoxic agent.
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PMID:Comparison of the effects of piperine administered intragastrically and intraperitoneally on the liver and liver mixed-function oxidases in rats. 189 51

Microcystin-LR, a cyclic heptapeptide synthesized by the blue-green algae, Microcystis aeruginosa, is a potent hepatotoxin. Pathological examination of livers from mice and rats that received microcystin-LR revealed severe, peracute, diffuse, centrilobular hepatocellular necrosis, and hemorrhage. These changes were correlated with increased serum activities of sorbitol dehydrogenase, alanine aminotransferase, and lactate dehydrogenase. Pretreatment of either rats or mice with a single dose of silymarin, a flavonolignane isolated from the wild artichoke (Silybum marianum L. Gaertn), completely abolished the lethal effects, pathological changes, and significantly decreased the levels of serum enzymes induced by microcystin-LR intoxication.
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PMID:Protection against microcystin-LR-induced hepatotoxicity by Silymarin: biochemistry, histopathology, and lethality. 190 64

This study characterized the effects of liver damage produced by a variety of hepatotoxicants on several components of the sulfation pathway in rats. Specifically, the concentration of cosubstrate, adenosine 3'-phosphate 5'-phosphosulfate (PAPS), and the hepatic capacity for PAPS synthesis were measured in livers of rats treated with carbon tetrachloride (CCl4), 1,1-dichloroethylene (DCE), alpha-naphthylisothiocyanate (ANIT), aflatoxin B1 (ATX), allyl alcohol (AA), bromobenzene (BB), cadmium chloride (Cd), or thioacetamide (TA). Liver damage was assessed by measuring serum sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALT) activities as well as by histopathological examination. Hepatic PAPS concentration was generally decreased as a result of treatment with hepatotoxicants (35-80% of control), although BB, AA, and ANIT were without effect. Maximal hepatic capacity for PAPS synthesis, determined as the activities of PAPS synthetic enzymes, ATP sulfurylase, and APS kinase, was selectively decreased by the hepatotoxicants. ATP sulfurylase activity was decreased by Cd and TA (55 and 62% of control, respectively), whereas APS kinase activity was decreased by Cd, TA, BB, and DCE (60-77% of control, respectively). In addition, phenol sulfotransferase (PST) activity was measured toward 1- and 2-naphthol in order to determine whether apparent changes in PST activity in damaged livers are substrate-dependent. Treatment with hepatotoxicants generally decreased 1-naphthol-directed PST activity but not PST activity directed toward 2-naphthol. In conclusion, (1) not all xenobiotic-induced liver injury results in decreased hepatic PAPS concentration, (2) some hepatotoxicants decrease PAPS concentration by a mechanism other than decreased cosubstrate synthesis, and (3) the effect of hepatotoxicants on PST activity is dependent upon the choice of substrate used in the enzymatic assay.
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PMID:The differential effects of hepatotoxicants on the sulfation pathway in rats. 194 7

The destruction of liver microsomal cytochromes P450 by a previously administered low dose of CCl4 has been widely accepted as the mechanism of CCl4 autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl4 (0.3 ml/kg, po) on the lethal effect of a subsequently administered high dose (5 ml/kg, po) was established in male Sprague Dawley rats. The protective dose permitted 100% survival, whereas only 15% survival was observed without it. Hepatotoxicity, measured by serum enzyme elevations (aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase) and histopathological changes 24 hr after the treatment with high dose, was similar in both the groups, even though the protective dose had significantly decreased liver microsomal cytochromes P450 (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl2 to decrease hepatic microsomal cytochrome P450 to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCl4. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCl4. Based on this observation, a premise that autoprotection results from augmented recovery from injury rather than decreased injury appears likely. Hence, the role of hepatocellular regeneration was evaluated by following 3H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl4, stimulated nuclear DNA synthesis measured by 3H-thymidine incorporation into nuclear DNA was increased and this remained high even after subsequent administration of high dose of CCl4. Forty-eight hr after the administration of a lethal dose of CCl4 alone (5 ml/kg, po), labelling index was slightly increased, but mitotic index was not increased. In the surviving rats (15%), both labelling index and mitotic index were significantly elevated after an additional 24 hr. In rats receiving the protective dose, a significantly greater elevation of labelling index as well as mitotic index occurred 48 hr after the administration of the same lethal dose of CCl4. These results suggest that hepatocellular regeneration stimulated by the protective dose, as a biological response recruited to overcome the accompanying limited injury, may augment and sustain tissue repair processes to permit tissue restoration even after the massive liver injury elicited by the subsequent large dose of CC14.
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PMID:Role of hepatocellular regeneration in CCl4 autoprotection. 204 7

Overdosage of acetaminophen (AA) is known to produce acute liver toxicity in both humans and laboratory animals. Hamsters are especially sensitive to the hepatotoxic effect of AA. In the present study, hamsters pretreated with pregnenolone-16 alpha-carbonitrile (PCN; 75 mg/kg, ip, daily for 4 days) were given a single dose of AA (350-1200 mg/kg, ip) and liver function was determined 24 hr later. Serum activities of alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) as well as histopathology were used as indices of hepatotoxicity. PCN pretreatment decreased AA-induced mortality. PCN dramatically decreased ALT (93-97%) and SDH (63-98%) activities relative to control values from hamsters treated with AA alone, and remarkably decreased hepatic centrilobular necrosis produced by AA. To investigate the mechanism of this protective effect, the biliary and urinary excretion of AA metabolites were measured for 1 hr after administration of AA (150 mg/kg, iv) in bile-duct-cannulated hamsters. PCN pretreatment resulted in increased urinary and biliary excretion of AA-glucuronide and decreased biliary excretion of AA-glutathione. Microsomes from PCN-pretreated hamsters produced less benzoquinoneimine intermediate than controls, as determined by the formation of AA-glutathione. In addition, hepatic UDP-glucuronic acid and UDP-glucuronosyltransferase were significantly increased in PCN-pretreated hamsters. In conclusion, PCN pretreatment protected against AA-induced hepatotoxicity. The mechanism of this protection appears to be due to decreased formation of the reactive metabolite by the cytochrome P450 pathway, and an increased detoxication by enhanced glucuronidation of AA.
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PMID:Protective effect of pregnenolone-16 alpha-carbonitrile on acetaminophen-induced hepatotoxicity in hamsters. 206 28

1,4-Butanediol (BAD) was administered to male and female Wistar Imp:DAK rats by oral gavage for 28 consecutive days. Treated rats received BAD at daily doses of 5, 50 or 500 mg/kg/day. After 28 days all animals were necropsied. Blood samples were obtained and selected organs were weighed and prepared for histological examination. Subacute oral administration of BAD resulted in an overall low degree of systemic toxicity. There were no changes in body weight, food consumption, and absolute and relative organ weights. Slightly higher activities of sorbitol dehydrogenase and alanine aminotransferase were observed in male rats given BAD at the highest dose of 500 mg/kg/day. Some disturbances in hematological parameters, characterized by macrocytosis and thrombocytopenia were observed in treated rats. Mild to moderate inflammation of the liver, characterized by proliferation of bile ducts and periportal infiltrations with fibroblasts and mononuclear cells, were found in treated animals. A statistically significant difference for histopathological changes was found in animals treated with BAD at the dose of 500 mg/kg/day only in the case where both sexes were jointly taken for comparison.
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PMID:Subacute oral toxicity of 1,4-butanediol in rats. 213 25

Rats were treated with trichloroethylene via intraperitoneal (ip) injection or inhalation, or with ip alpha-naphthylisothiocyanate (ANIT). Serum samples were assayed for indices of liver injury including alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), alkaline phosphatase (AP), and bilirubin. Liver from some rats was examined for histological appearance. These data were compared to levels of individual serum bile acids (SBA) determined by high-performance liquid chromatography. Trichloroethylene and ANIT, each at their highest dose only, caused elevations in ALT, but not SDH or AP. The highest dose of ANIT also caused elevated serum bilirubin and cholangitis in the liver. SBA were also elevated in response to both trichloroethylene and ANIT, but at doses below those at which other parameters of liver function were increased. For both chemicals, taurocholic acid was the most sensitive of the bile acids assayed, being elevated at the lowest doses tested of 10 mumols/kg for trichloroethylene and 5 mumols/kg for ANIT. As the doses were raised more of the individual bile acids showed increases. On exposure to trichloroethylene via inhalation taurocholic acid was one of two SBA to show elevation. Thus, both trichloroethylene and ANIT cause elevation in SBA at doses well below those which cause an increase in standard indicators of liver dysfunction. This suggests that SBA and perhaps taurocholic acid, in particular, may provide a sensitive tool for studying hepatobiliary effects of chemicals.
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PMID:Elevation of individual serum bile acids on exposure to trichloroethylene or alpha-naphthylisothiocyanate. 221 16

Quail were fed monensin to determine liver damage, as measured by changes in activities of serum enzymes and liver microsomal enzymes. Monensin fed at a therapeutic level of 110 ppm for 2 weeks produced an increase in cytochrome P-450 and cytochrome b5 and induction of the activities of benzphetamine N-demethylase, aminopyrine N-demethylase, and aniline hydroxylase, with no changes in the activities of serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). On the other hand, quail fed 110 ppm, 220 ppm, and 330 ppm monensin in feed for 6 weeks showed a significant rise in SDH and AST activities at 330 ppm but not at 110 ppm and 220 ppm. The manifestations of liver toxicity observed at 330 ppm were accompanied by a significant decrease in all the aforementioned hepatic microsomal mixed-function oxidases. In contrast, quail fed monensin at 110 ppm and 220 ppm for 6 weeks produced no change in these parameters except for benzphetamine N-demethylase, aminopyrine N-demethylase, and aniline hydroxylase, which were significantly increased in birds fed 220 ppm of monensin.
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PMID:Toxicity of dietary monensin in quail. 224 82


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