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)

Fasted male rats were given six doses of 14CCl4 ranging from non-hepatotoxic (0.1 mmole/kg) to severely hepatotoxic (26 mmoles/kg). Time-course and pharmacokinetics of CCl4, 14CO2 and CHCl3 elimination by exhalation were monitored by measuring amounts recovered in breath during discrete 15-min intervals for 8-12 hr. Amounts of 14C-labeled metabolite recovered bound to liver macromolecules at 24 hr and excreted in urine or feces for 24 hr were also determined. Comparison pharmacokinetic studies were done with 14CHCl3 and Na(2)14CO3. After all doses of 14CCl4, the major metabolite was CO2, twenty to thirty times less metabolite was recovered bound to liver macromolecules, and intermediate amounts of metabolite were excreted in urine and feces. CHCl3 was the least abundant metabolite at low CCl4 doses, but the second most abundant at high doses. Stronger associations were found between the magnitude of liver injury at 24 hr (quantitated as serum glutamate-pyruvate transaminase activity) and the extent or rate of CCl4 metabolism by pathways leading to CO2 and CHCl3 than by pathways leading to 14C-metabolites bound in liver or excreted in urine. Time-course and pharmacokinetic data indicated that a major pathway of CCl4 metabolism leading to CO2 became impaired within 2 hr after administration of hepatotoxic doses of CCl4.
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PMID:Metabolism of [14C]carbon tetrachloride to exhaled, excreted and bound metabolites. Dose-response, time-course and pharmacokinetics. 643 7

The renal and hepatotoxicities of five selected halomethanes, which are drinking water contaminants, were evaluated following a 14-day exposure. Bromodichloromethane, bromoform, chloroform, dibromochloromethane and methylene chloride were administered at three dose levels. Toxicity was evaluated by measuring changes in total body weight, uptake of p-aminohippurate into renal cortical slices, blood urea nitrogen, serum creatinine, and serum glutamate-pyruvate transaminase levels and by performing a histopathologic examination of liver and kidney tissues. Dose-related effects on the liver and kidney were detected with the uptake of p-aminohippurate into kidney slices and with the histopathologic evaluation of tissues. Treatment-related effects seen in the methylene chloride exposed mice were less pronounced as compared to the other halomethane treatment groups. In general, histopathological changes were the most sensitive indicators of both liver and kidney damage.
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PMID:Comparative renal and hepatotoxicity of halomethanes: bromodichloromethane, bromoform, chloroform, dibromochloromethane and methylene chloride. 665 42

Liver damage was investigated in rat using serum enzyme activities measurements. Responses were recorded 24 h after whole body inhalation exposure to vapors of bromobenzene, carbon tetrachloride, chloroform, o-dichlorobenzene, 1,2-dichloroethane and dimethylformamide as model toxicants. First, rats were exposed during a single 4 h period to different concentrations of each solvent and the minimally active concentration was determined. Second, repeated exposures to chemicals at this concentration level (6 h daily, 2 or 4 days) were used in order to examine whether hepatotoxicity was enhanced. GLDH and SDH are more sensitive and more constant indices than GOT and GPT. It appears that a single exposure period induced more marked serum activities enhancement than repeated exposures.
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PMID:Short-term inhalation test for evaluating industrial hepatotoxicants in rats. 665 18

The effects of promethazine (PM) on different aspects of the hepatotoxic action of CCl4 in the rat were investigated with the objective of finding rapid and reliable indicators of hepatoprotective effects. The study was based on definitive histological assessment of liver damage caused by CCl4 in the presence and absence of PM: PM (78 mumol kg-1, i.p.) protected against CCl4-induced hepatic necrosis 24 h after a low dose of CCl4 (1.3 mmol kg-1) but not against a higher dose (13.0 mmol kg-1). The large increases in plasma activities of GOT, GPT and LDH produced by dosing with CCl4 were partially inhibited by the administration of PM. PM and CCl4 caused a synergistic and long-lasting decrease in body temperature (2-3 degrees C for 8-10 h). Modifying the toxicity with PM, together with a low dose of CCl4, helped to minimize secondary effects of CCl4, to clarify the sequence of toxic events, and to assess the sensitivity of some standard tests of hepatotoxicity. Simultaneous measurement of over 20 commonly used biochemical screening tests in individual animals 3 or 6 h after treatment permitted direct correlation of a wide variety of concentrations, activities and effects. For example, liver CHCl3 concentrations (as a measure of CCl4 metabolism) correlate strongly with increases in diene conjugation of microsomal lipids (as a measure of CCl4-induced lipid peroxidation); malonaldehyde production appears to be less sensitive as a measure of lipid peroxidation in vivo than diene conjugation. The changes induced in each parameter and the correlations between them are discussed with reference to the overall nature of the hepatotoxic reaction and its modification by PM.
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PMID:Correlations between common tests for assessment of liver damage: indices of the hepatoprotective activity of promethazine in carbon tetrachloride hepatotoxicity. 667 18

There is increasing evidence to show that drug metabolism and effects are modulated by biological rhythms; therefore the possibility that chloroform (CHCl3) induced acute hepatotoxicity may also vary as function of time of administration was investigated in male Sprague--Dawley rats. The animals were given a single intraperitoneal dose of CHCl3 or saline, 0.5 ml/kg, at 09:00 h, 13:00 h, 17:00 h, 21:00 h or 03:00 h and killed 4 h after treatment. The hepatotoxicity induced by CHCl3 was determined by the serum glutamic-pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH) activities and by the glucose-6-phosphatase (G6Pase) activity of the liver. The increases in SGPT, SGOT and LDH were minimal and maximal when the organic solvent was injected at 09:00 h and 21:00 h, respectively, whilst the activity of G6Pase was depressed significantly at 03:00 h and 13:00 h under similar conditions. Starving the rats for 16 h prior to the injection of CHCl3 at 09:00 h increased substantially the hepatotoxicity as measured by the above enzyme activities. These findings may be relevant in the toxicity of CHCl3 in industrial workers exposed to this solvent at various times of the day.
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PMID:Temporal variations in chloroform-induced hepatotoxicity in rats. 685 99

Previous studies have suggested that ketonic solvents potentiate the hepatotoxic action of CHCl3 in rats. In addition, the relative potentiating capacity of the ketones appeared to be related to the length of their carbon skeleton. To test this hypothesis CHCl3-induced liver injury was evaluated in male Sprague-Dawley rats pretreated (15 mmol/kg, p.o.) with acetone (Ac), 2-butanone (Bu), 2-pentanone (Pn), 2-hexanone (Hx) or 2-heptanone (Hp). After 18 h, a challenging dose of CHCl3, (0.50 or 0.75 ml/kg, i.p.) was given. Liver damage was evaluated 24 h after CHCl3 administration by determining elevations in plasma GPT and OCT activity. Neither Ac, Bu, Pn, Hx, Hp or the CHCl3 challenging dosages produced marked liver injury when given alone. However, each of the ketones potentiated CHCl3-induced liver damage. The severity of the potentiated hepatotoxic response was significantly (positively) correlated with the ketone carbon chain length. These observations suggest that carbon skeleton length may play a role in determining the relative potentiating capacity of ketonic solvents.
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PMID:Relationship between the carbon skeleton length of ketonic solvents and potentiation of chloroform-induced hepatotoxicity in rats. 685 25

The effect of hypoxia on carbon tetrachloride-induced hepatotoxicity was studied. Male rats were exposed to carbon tetrachloride for 2 hr in the presence of differing oxygen concentrations. Serum glutamate-pyruvate transaminase (SGPT) activities were measured 24 hr after the end of the exposure. Exposure of rats to 5000 ppm carbon tetrachloride in the presence of 100, 21, 12, or 6% oxygen resulted in SGPT activities of 489, 420, 3768, and 1788 I.U./l respectively. Exposure of rats to air and 0, 1250, 2500, 5000, or 7500 ppm carbon tetrachloride gave SGPT activities of 35, 32, 69, 420, and 2188 I.U./l respectively; when 12% oxygen was used, the corresponding SGPT activities were 32, 665, 691, 3768, and 4200 I.U./l respectively. Exposure of rats to hypoxia produced histopathologically detectable condensation of hepatic cytoplasmic material, and exposure to 5000 ppm carbon tetrachloride in the presence of air produced mild centrilobular necrosis, which was much more severe when rats were exposed to 5000 pm carbon tetrachloride in the presence of 12% oxygen. Hepatic microsomal conjugated diene concentrations were increased by hypoxia and by exposure to carbon tetrachloride, but no synergistic interaction was observed. Hepatic microsomal cytochrome P-450 concentrations were decreased after exposure to carbon tetrachloride, but were the same after exposure to carbon tetrachloride and 12 or 21% oxygen. Hepatic carbon tetrachloride concentrations were the same in rats exposed to carbon tetrachloride in the presence of 12 or 21% oxygen; hepatic chloroform concentrations were higher in rats exposed to carbon tetrachloride in the presence of air than in the presence of 12% oxygen. The covalent binding of [14C]carbon tetrachloride metabolites to hepatic microsomal lipids and proteins was increased markedly by hypoxia as compared with normoxia. The covalent binding of metabolites of carbon tetrachloride to cellular macromolecules may play a role in the potentiation of carbon tetrachloride toxicity by hypoxia.
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PMID:Effect of hypoxia on carbon tetrachloride hepatotoxicity. 715 61

The effect of hepatectomy on the hepatotoxic effect of halogenated hydrocarbons was studied. Male rats received oral administration of chloroform of carbon tetrachloride at a single dose of 500 mg/kg, 3 days prior to or after the partial hepatectomy. The hepatotoxic effect of the toxins was modified in a different manner according to the time of the hepatectomy. In the animals hepatectomized 3 days after the hepatotoxins administration, histological changes of the liver were similar to those of the non-hepatectomized rats, except with an increase in the activity of GOT and GPT. Contrary, in the animals hepatectomized 3 days prior to the hepatotoxins administration, the toxic effect of the chemicals was less enhanced than in the non-hepatectomized animals.
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PMID:[Modification of hepatotoxic effect of halogenated hydrocarbons on partially hepatectomized rats (author's transl)]. 730 46

Chloroform (CHCl3) produces renal and hepatic damage in humans and experimental animals. Deuterium-labeled chloroform (CDCl3) has been reported to be less hepatotoxic than CHCl3 in rats. However, this isotope effect has not been determined in other species or in extrahepatic tissues. In this investigation, the effect of deuterium substitution on the nephrotoxicity and hepatotoxicity of CHCl3 was quantified in male ICR mice. Renal and hepatic damage were determined 24 h after administration on various doses of CHCl3 or CDCl3. Liver damage was estimated by measuring serum glutamic-pyruvic transaminase (SGPT) activity. Nephrotoxicity was evaluated by measuring blood urea nitrogen (BUN) and in vitro renal cortical accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA). Dose-related hepatotoxicity and nephrotoxicity were observed after administration of CHCl3 and CDCl3. CDCl3 produced less liver damage than CHCl3 in mice, suggesting that mouse liver metabolizes CHCl3 by the same mechanism as rat liver. CDCl3 was also less toxic to kidneys than CHCl3, suggesting that the kidney may metabolize CHCl3 in the same manner as the liver
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PMID:Nephrotoxicity and hepatotoxicity of chloroform in mice: effect of deuterium substitution. 732 96

Mice were administered with chloroform at 10 a.m., 2 p.m. and 6 p.m. and the signs of hepatotoxicity were measured 18 or 24 hrs later. The levels of alanine aminotransferase (ALT) in serum, and malondialdehyde (MDA) in the liver were higher after the evening administration compared to the morning one. The decrements of reduced glutathione (GSH) levels in the liver followed a similar pattern. It is concluded that the susceptibility of mice to the toxic effect of chloroform follows a circadian rhythm.
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PMID:The diurnal rhythm of hepatotoxic action of chloroform. 758 50


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