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 hypothesis that the prior intake of barbiturates may predispose patients to form increased amounts of oxalate following the intravenous infusion of xylitol was investigated in the rat. Phenobarbitone pre-treatment resulted in a 2-3 fold increase in urinary [14C] oxalate concentration following the intraperitoneal injection of [U-14C] xylitol or [l -14C] glycollate. The absence of any marked changes in urine volumes and creatinine excretion implied that this increase in urinary oxalate excretion was due to the enhanced synthesis of oxalate. The activities of key enzymes in hepatic oxalate synthesis, glycollate oxidase, lactate dehydrogenase, catalase and alanine aminotransferase were not altered by phenobarbitone pre-treatment. It is suggested that the increased activity of the microsomal mixed function oxidases, following phenobarbitone treatment, may facilitate the oxidation of glycollate and possibly xylitol. This communication leads experimental support to the concept that the prior intake of drugs, such as barbiturates, may predispose patients to form increased amounts of oxalate.
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PMID:Oxalate excretion in rats injected with xylitol or glycollate: stimulation by phenobarbitone pre-treatment. 48 83

The acute hepatotoxicity of the three isomers of dichlorobenzene (DCB) was evaluated in male Fischer-344 (F344) rats at various times following ip administration. Plasma alanine aminotransferase (ALT) activity, measured in F344 rats 24 hr postexposure, was dramatically elevated following doses of 1.8-5.4 mmol/kg of o-DCB. Conversely, equimolar doses of p-DCB produced no such toxicity, while m-DCB produced intermediate hepatic injury at or above doses of 2.7 mmol/kg. Histopathological changes in livers from treated animals qualitatively reflected elevations in 24-hr plasma ALT activity (time to maximal elevation). Phenobarbital pretreatment potentiated the acute hepatotoxicity of o- and m-DCB, but did not affect the toxicity of p-DCB. Likewise, SKF-525A pretreatment inhibited the hepatotoxicity of o-DCB. Equimolar doses of o- and m-DCB produced approximately equivalent depletion of intrahepatic glutathione, while p-DCB had no effect on hepatic GSH. Furthermore, prior depletion of hepatic glutathione by pretreatment with phorone markedly potentiated the hepatotoxicity of o- and m-DCB, while increasing the toxicity of p-DCB to a far lesser degree. The differential hepatotoxicity of the o- and m-DCB does not appear to be explained adequately by differences in their hepatic distribution or in vivo covalent binding to hepatic proteins. Interestingly, male Sprague-Dawley (SD) rats are relatively refractive to the acute hepatotoxicity of o-DCB following ip administration of 1.8 and 5.4 mmol/kg. The combination of these dramatic differences (structure-activity and animal strains) should be useful in elucidating key events involved in the hepatotoxicity caused by these compounds.
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PMID:The acute hepatotoxicity of the isomers of dichlorobenzene in Fischer-344 and Sprague-Dawley rats: isomer-specific and strain-specific differential toxicity. 185 46

Phenobarbitone pretreatment potentiated hepatocyte lesions in male rats 24 hr after treatment with 1-fluoropentane (3.5 mg/kg body weight) and 1-fluorohexane (0.17 mg/kg body weight). Serum levels of the enzymes ornithine carbamyltransferase, glutamic-pyruvic transaminase and gamma-glutamyltranspeptidase were significantly elevated by the test compounds with the peak effect occurring 24-72 hr after a single ip administration. Significant elevation of hepatocyte triglyceride content and mitochondrial calcium and citrate levels were demonstrated 24 and 48 hr after a single ip injection of 1-fluoropentane or 1-fluorohexane, respectively.
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PMID:A comparative study of the hepatotoxicity of 1-fluoropentane and 1-fluorohexane. 319 37

Cocaine-induced hepatotoxicity was examined in vivo in a dose-responsive manner in C57BL/6Ibg, DBA/2Ibg, C3H/2Ibg, and Balb/cJ mice. Serum glutamic-pyruvic transaminase (SGPT) activities were determined 24 hours after intraperitoneal (IP) administration of cocaine (20 to 100 mg/kg). Significant elevations (100- to 150-fold) in SGPT were observed in male mice receiving cocaine. Significant differences in sensitivity to cocaine-induced hepatotoxicity were found among males of the inbred strains, with Balb being most sensitive and C57BL being least sensitive and C3H and DBA strains exhibiting intermediate sensitivity. Female mice of the four inbred strains were more resistant than males to cocaine-mediated hepatotoxicity, as indicated by only twofold to tenfold elevations in SGPT values. Among the females, sensitivity of the four inbred strains--as indicated by dose response curves--fell into two categories: the sensitive strains (C3H and C57BL) and the resistant strains (Balb and DBA). Pretreatment of males of the four inbred strains with the P-450 inducer phenobarbital resulted in enhancement of cocaine-mediated hepatotoxicity in the C57BL and Balb but not the C3H and DBA mice. Phenobarbital pretreatment of females of the four inbred strains resulted in enhancement of the hepatotoxic response to cocaine in the C3H, DBA, and Balb mice. Phenobarbital-pretreated C57BL females exhibited a 100% mortality rate after the acute cocaine dose, and thus no determination of hepatotoxicity could be established for them. These data demonstrate sex and strain differences in cocaine-induced hepatotoxicity and suggest that phenobarbital pretreatment does not uniformly enhance the hepatotoxicity of cocaine.
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PMID:Sex and strain differences in the hepatotoxic response to acute cocaine administration in the mouse. 323 36

The ability of trichloroethylene (TCE) and selected metabolites to induce single-strand breaks in hepatic DNA of male B6C3F1 mice and Sprague-Dawley rats in vivo was evaluated using an alkaline unwinding assay. Doses of TCE of 22-30 mmol/kg were required to produce strand breaks in DNA in rats, whereas a dose of 11.4 mmol/kg was sufficient to increase the rate of alkaline unwinding in mice. To assess the importance of TCE metabolism to this response, rats were subjected to pretreatments of ethanol, phenobarbital, TCE, or the appropriate vehicle for 4 days prior to challenge doses of TCE. Phenobarbital and TCE, but not ethanol pretreatments, reduced the dose of TCE required to produce significant increases in single-strand breaks. In another series of experiments, mice and rats were treated with metabolites of TCE. Trichloroacetate, dichloroacetate, and chloral hydrate induced strand breaks in hepatic DNA in a dose-dependent manner in both species. Strand breaks in DNA were observed at doses that produced no observable hepatotoxic effects as measured by serum aspartate aminotransferase and alanine aminotransferase levels. The slopes of the dose-response curves and the order of potency of these metabolites differed significantly between rats and mice, suggesting that different mechanisms of single-strand break induction may be involved in the two species. These data provide a potential explanation for the different sensitivity of mice and rats to the hepatocarcinogenic effects of TCE.
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PMID:Induction of strand breaks in DNA by trichloroethylene and metabolites in rat and mouse liver in vivo. 337 13

The purpose of this investigation was to correlate the in vitro and in vivo toxicity of the hepatotoxicant, acetaminophen. Hamsters were pretreated with either phenobarbital (70 mg/kg) or 3-methylcholanthrene (20 mg/kg) or an appropriate vehicle for 3 days. In non-pretreated hamsters, single doses of acetaminophen (200-400 mg/kg i.p.) caused elevations in serum alanine aminotransferase and sorbitol dehydrogenase activities in a dose-related manner. 3-Methylcholanthrene significantly potentiated, while phenobarbital significantly reduced acetaminophen-induced elevations in serum liver enzyme activities. Both phenobarbital and 3-methylcholanthrene significantly reduced acetaminophen plasma T1/2 while only 3-methylcholanthrene increased APAP clearance. Phenobarbital pretreatment increased the urinary excretion of APAP-glucuronide. Exposure of isolated hepatocytes to acetaminophen (0.01-2.0 mM) resulted in concentration-related decreases in hepatocyte viability. Cells from 3-methylcholanthrene-pretreated hamsters were more markedly susceptible to acetaminophen toxicity than cells isolated from non-induced animals. Hepatocytes isolated from phenobarbitol pretreated animals were slightly but significantly more susceptible to acetaminophen toxicity than cells from control animals. Hepatocytes isolated from 3-methylcholanthrene pretreated animals had increased formation of an acetaminophen-glutathione conjugate compared to control. Pre-treatment with either phenobarbital or 3-methylcholanthrene enhanced glucuronidation of acetaminophen in vitro. These data demonstrate a lack of correlation between in vivo hepatotoxicity and in vitro cytotoxicity in that phenobarbital pre-treatment protected hamsters from acetaminophen-induced liver toxicity, but failed to protect hepatocytes exposed to acetaminophen in vitro.
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PMID:In vivo and in vitro hepatotoxicity and metabolism of acetaminophen in Syrian hamsters. 356 56

The effects of two promoters of hepatocarcinogenesis--phenobarbital and butylated hydroxytoluene (BHT)--on five hepatic biochemical parameters were examined in adult female rats. Phenobarbital given orally in two doses each of 110 mg/kg 21 and 4 hr before the rats were killed caused large increases in hepatic ornithine decarboxylase (ODC) activity and cytochrome P-450 content. Extending the number of phenobarbital treatments to five increased the hepatic enzyme induction and also caused a minor decrease in hepatic glutathione and a small increase in serum alanine aminotransferase activity. Two oral doses of 700 mg BHT/kg (20% of the LD50) caused hepatic DNA damage and induction of both ODC activity and cytochrome P-450 content. When the dose of BHT was reduced from 700 to 140 mg/kg no significant effects on the biochemical parameters were found. Both promoters of hepatocarcinogenesis were identified by their induction of ODC, a marker for promotional potential, but only BHT showed a potential for carcinogenic initiation. The biochemical parameters examined, particularly the alkaline elution technique for DNA damage, ornithine decarboxylase activity and serum alanine aminotransferase, may constitute a useful assay system for examining a compound's potential for carcinogenic initiation, carcinogenic promotion and cellular toxicity.
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PMID:Biochemical effects of two promoters of hepatocarcinogenesis in rats. 362 51

The present study extends previous reports of hepatic damage 24 h after halothane anaesthesia in the phenobarbitone pretreated hypoxic rat model by fully characterizing the lesion during the time course of its onset and recovery. Phenobarbitone treated animals exposed to halothane (1% for 2 h in 14% inspired oxygen) were killed 1, 2, 4, 6, 12 and 24 h and 2, 3, 5, 10, 15 and 30 days after commencement of the anaesthetic period. Blood was collected 1 day before the administration of halothane and at the time of killing for determination of serum alanine aminotransferase (ALT), a biochemical index of hepatic damage. Liver tissue was obtained immediately at post-mortem for histological examination. Serum ALT was increased at the end of the anaesthetic period, i.e. 2 h, with peak levels occurring at 12-24 h and remaining elevated for 3 days after exposure. Minor changes in liver histology were evident at 2 h in 50% of the animals and by 6 h all animals had mild hepatic injury. The extent of the necrosis was maximal at 24 h and this was sustained until 3 days. By 5 days after exposure minimal evidence of liver damage was observed and animals killed at 30 days had morphologically normal livers. Elevation of serum ALT or changes in liver histology were not observed in other treatment groups. The early onset of damage at 2-6 h is in keeping with direct hepatotoxicity associated with the biotransformation of halothane.
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PMID:Halothane hepatitis in an animal model: time course of hepatic damage. 368 69

An experimental animal model designed specifically to simulate liver fibrosis and cirrhosis in childhood is described. Phenobarbitone was administered continuously from the 4th day of life and carbon tetrachloride intermittently from the 13th day to developing rats for 10 weeks. Treated animals showed hepatic necrosis, hepatic regeneration and a progressive increase in hepatic fibrosis; cirrhosis developed before the animals reached sexual maturity at 72 days or were fully grown. Hepatic prolyl hydroxylase activity increased to a maximum level after 20 days of treatment, before increased hepatic collagen could be detected, and fell to a lower level as cirrhosis became established. Serum activities of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase gave a similar pattern, a marked increase at 20 days of age followed by a fall to near normal levels as hepatic damage became more severe. By the 26th day of life hepatic collagen levels were increased significantly and rose thereafter progressively as fibrosis became more widespread throughout the liver. Cirrhosis developed between the 38th and 75th days. Cirrhosis remained 10 weeks after discontinuation of treatment with phenobarbitone and carbon tetrachloride treatment.
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PMID:Carbon tetrachloride-induced hepatic fibrosis and cirrhosis in the developing rat: an experimental model of cirrhosis in childhood. 630 21

To study the relationship between lipid peroxidation and cellular damage we studied three compounds known to evoke lipid peroxidation (cumene hydroperoxide, CHP), hepatocellular injury (thioacetamide, TAA) or both (carbon tetrachloride, CCl4). Phenobarbital-induced male rats were treated with one of the three agents and lipid peroxidation was monitored via the measurement of exhaled ethane. Treatment with both, CCl4 and CHP resulted in an increased ethane expiration, whereas TAA did not. When liver-specific serum enzyme activities (GPT, SDH) were investigated 24 h later, however, hepatotoxicity was evident only in rats treated with either CCl4 or TAA. The ATP-dependent Ca2+-sequestration activity of microsomal membranes, suggested to be a final common pathway leading to cellular death, was studied in microsomes isolated from rats treated with either agent. 2 h after treatment with CCl4 or TAA a clear inhibition was seen which persisted after 24 h in the case of CCl4 only. CHP did not affect the Ca2- -pump activity. Thus, a clear correlation between cellular damage and lipid peroxidation cannot be expected in every case. An impairment of the microsomal calcium-pump, however, seems to be a crucial event which leads to hepatocellular injury.
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PMID:Interrelationship between in vivo lipid peroxidation, microsomal Ca2+-sequestration activity and hepatotoxicity in rats treated with carbon tetrachloride, cumene hydroperoxide or thioacetamide. 662 17


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