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 photodegradation of chlorpromazine, a drug frequently used in psychotherapy, was examined under different sets of experimental conditions. A primary culture of rat hepatocytes was used to evaluate the possible hepatotoxicity of the chlorpromazine photoproducts, keeping in mind the following criteria: leakage of cytosolic enzymes; attachment index to culture plates, and albumin synthesis. Cells exposed to concentrations greater than 10(-4) M of the photomixtures showed extensive leakage of GOT and GPT into the culture medium and, at the same time, the cell attachment was seriously impaired. A concentration of 10(-7) M of the photoproducts proved capable of inhibiting the synthesis of albumin (20%). Photoproducts obtained after aerobic irradiations were as toxic for hepatocytes as those found in anaerobic conditions. The implications of our results in connection with the relevance of oxygen-dependent photoreactions of chlorpromazine to its phototoxicity, and the possible appearance of hepatic alterations in patients treated with the drug after exposure to the sunlight, are discussed.
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PMID:Toxic effects of the photoproducts of chlorpromazine on cultured hepatocytes. 355 16

In a randomized prospective controlled study in humans, the metabolism and hepatic effects of a single administration of halothane were compared with enflurane and meperidine. Pre- and postoperative antipyrine pharmacokinetics, intraoperative indocyanine green clearance, liver histology, and postoperative liver function tests were determined in 24 patients undergoing abdominal surgery who were randomly allocated to receive either halothane (0.5%, group I), enflurane (0.8%, group II), or meperidine (group III) as a supplement to a common basal anesthetic regimen consisting of thiopental, nitrous oxide/oxygen/muscle relaxant. In addition, end-tidal concentrations of the volatile reductive metabolites of halothane, chlorodifluoroethylene (CDF), and chlorotrifluoroethane (CTF) were determined in group I patients and serum and urinary inorganic fluoride were determined in both group I and II patients. Indocyanine green clearance was measured before anesthesia (stage I), during basal anesthesia (stage II), in the presence of surgical stimuli (stage III), and after introduction of the selected anesthetic agent (stage IV). CDF and CTF were detectable within 20 min of the start of halothane anesthesia in every patient receiving halothane. Peak serum fluoride concentrations occurred at 2 and 24 hr in the enflurane and halothane groups, respectively, whereas urinary fluoride excretion was elevated postanesthesia in the enflurane group only. There was no difference between the pre- and postoperative disposition of antipyrine in group II or III, but after anesthesia, antipyrine clearance was significantly decreased (P less than 0.02) and plasma half-life increased (P less than 0.05) in group I patients (halothane). Concentrations of serum alanine aminotransferase (ALT) and bilirubin were significantly elevated (P less than 0.5) postoperatively in groups I and II but unchanged from preoperative values in group III patients. Three of the 24 liver biopsies taken at the end of stage IV showed several foci of acute liver cell necrosis; of these, two patients were from group I and one from group II. There were no significant differences in liver cell morphology (P greater than 0.5) in biopsies taken at the end of stage IV compared with biopsies at the end of stage III, from groups I and II. The results of this study show that reductive metabolism of halothane occurs routinely in patients undergoing halothane anesthesia under conditions of normoxia. This may be the cause of the changes in antipyrine clearance after halothane anesthesia.
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PMID:A randomized prospective controlled study of the metabolism and hepatotoxicity of halothane in humans. 356 92

Ethanol at initial concentrations between 0.75 and 6 g/l produced a dose-dependent release of the enzymes glutamic-pyruvic-transaminase and sorbitol dehydrogenase (GPT, SDH) from the isolated perfused rat liver. At the concentration of 6 g/l, it also decreased the oxygen consumption and elevated the calcium content of the isolated livers. These toxic effects of ethanol were significantly enhanced in livers, the glutathione content of which had been depleted by pretreatment with phorone. Ethanol-induced toxicity in glutathione-depleted isolated livers could be prevented both by inhibition of alcohol dehydrogenase with 4-methylpyrazole and of xanthine oxidase with allopurinol. In rats, in vivo, 1.6 g/kg ethanol injected intravenously produced a small increase in serum GPT and SDH concentrations 4 h after its administration. This increase in enzyme activities was several-fold higher and longer lasting in rats pretreated with phorone. Glutathione depletion per se did not induce hepatotoxicity in vitro or in vivo. Since glutathione is involved in several lines of defense against oxidative damage, our results of an enhanced susceptibility of glutathione-depleted livers to ethanol toxicity favour the hypothesis that ethanol exerts its hepatotoxic action via an activation of molecular oxygen.
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PMID:Enhancement by glutathione depletion of ethanol-induced acute hepatotoxicity in vitro and in vivo. 360 86

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

The role of calcium in allyl alcohol-induced hepatotoxicity was investigated in the isolated haemoglobin-free perfused rat liver. At a Ca++ concentration of 2.5 mmol/l in the perfusate, allyl alcohol (initial concentration 1.17 mmol/l) produced an enhanced release of GPT and SDH from the liver, an increase in the lactate/pyruvate ratio of the perfusate, a decrease in hepatic oxygen consumption and an increase of both hepatic calcium and malondialdehyde content. In the absence of Ca++ in the perfusate, no hepatic calcium accumulation occurred with allyl alcohol, but all other signs of hepatic damage were as severe as with 2.5 mmol/l Ca++. On the other hand, high extracellular Ca++ (5 mmol/l) alone led to a threefold increase of liver calcium but produced only marginal hepatotoxicity and only slightly enhanced the hepatotoxic effects of allyl alcohol. The concentrations of allyl alcohol in the perfusate were not altered at different Ca++ concentrations. In conclusion, the primary allyl alcohol-induced hepatotoxic injury does not appear to depend upon an influx of extracellular calcium.
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PMID:Influence of extracellular calcium on allyl alcohol-induced hepatotoxicity. 376 50

Three 4-hr normoxic (21% oxygen) exposures to 1% halothane administered 3 days apart were associated with elevations in serum alanine aminotransferase (ALT) activity in four of 20 guinea pigs after the initial and third exposures. Serum alanine aminotransferase values were not measured after the second anesthetic. Susceptibility was defined as an ALT level greater than 300 IU/L after halothane. Nonsusceptible animals, that is, animals without significant increases in ALT values after halothane, remained nonsusceptible after reexposure. Serum alanine aminotransferase values after the first and third anesthesias were significantly correlated (rs = 0.86, P less than 0.001). Two exposures of another 30 guinea pigs at a 5-week interval resulted in high elevations of ALT in the same eight animals after both anesthetics. In contrast, after an initial exposure nonsusceptible animals remained nonsusceptible upon reexposure. Serum alanine aminotransferase levels after the first and second anesthetics were significantly correlated (rs = 0.85, P less than 0.001). The proportion of first generation (F1) males with elevated ALTs whose parents were susceptible to halothane hepatotoxicity (HH) was significantly higher than the proportion of males with elevated ALTs in a random group of 90 males (P less than 0.005). First generation males and females of nonsusceptible parents had ALTs within the normal range after halothane exposure. These studies suggest that in the guinea pig genetic predisposition is an important determinant of susceptibility to HH, although other contributing factors are not excluded.
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PMID:Genetic predisposition to liver damage after halothane anesthesia in guinea pigs. 376 12

Rats which had approximately 25-30% of their calculated blood volume removed were exposed to halothane (1%) or enflurane (2%) in 33% oxygen for 30 min. Hepatic function was evaluated by determining, at various time intervals, serum activities of glutamic-oxalacetic and glutamic-pyruvic transaminase, acid phosphatase and gamma-glutamyl-transpeptidase. In this model serum enzyme activities and animal mortality were significantly increased when hypovolemic hypotension was induced during halothane anaesthesia. The same events did not occur in bleeding animals anaesthetized with enflurane. The marked disparity in hepatic dysfunction and mortality between halothane and enflurane-anaesthetized rats during hypovolemic hypotension may be explained by the more pronounced decrease of oxygen available for the liver and production of reductive toxic intermediates in animals exposed to halothane.
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PMID:Liver function following hypovolemic hypotension in rats anaesthetized with halothane or enflurane. 379 49

To determine the cause of hepatic injury in patients with hypoxaemia, the persistence of liver susceptibility to toxic injury after hypoxia was investigated in rats. Centrilobular necrosis and marked elevation of serum glutamic-pyruvic transaminase (SGPT) and serum glutamic-oxaloacetic transaminase (SGOT) activities were induced by carbon tetrachloride (0.1 ml/kg body weight) given in the period between 3 h before and 21 h after exposure to 7% oxygen for 3 h. This observation, that a short period of hypoxia results in a prolonged sensitivity to carbon tetrachloride-induced liver injury, has not been described previously. The mechanism of the phenomenon is obscure. These observations suggest that the hepatic injury in patients with hypoxaemia may be caused not only by the hypoxia per se or chemicals administered before or during hypoxia, but also by chemicals given within 24 h of hypoxaemia.
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PMID:Potentiation of carbon tetrachloride hepatotoxicity by hypoxia. 380 2

Changes in three recognized liver function tests are reported following the use of propofol in 30 fit, unpremedicated women in whom propofol was used as the main anaesthetic agent. Doses of 140 to 330 mg were given, together with nitrous oxide and oxygen. All patients were undergoing minor gynaecological operations and all conformed to Grade 1 physical status of American Society of Anesthesiologists Classification. In none of these patients was there hypoxia or hypercarbia at any time during or following anaesthesia and none of the patients received any other drugs until completion of the study. No significant changes in liver enzymes (aspartate transaminase and alanine transaminase) or in serum alkaline phosphatase were detected.
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PMID:Changes in liver function tests after propofol ('Diprivan'). 387 86

Halothane anesthesia (1%) administered in 21% oxygen for 4 hr to an outbred strain of guinea pig in the absence of enzyme induction resulted in liver damage in 40 of the 65 animals studied. Necrosis was either confluent around the central veins or in scattered foci throughout the lobules. Damage was present on the second and third days after anesthesia. By day 7 the livers had recovered, evidenced by lack of histological changes and normal serum alanine aminotransferase activity. Administration of halothane in 14 or 80% inspired oxygen did not alter the extent or incidence of liver damage. Major end-metabolites of halothane biotransformation (2-chloro-1,1-difluoroethylene, 2-chloro-1,1,1-trifluoroethane, inorganic fluoride and trifluoroacetic acid) were identified at each oxygen concentration. The metabolic inhibitor SKF-525A significantly decreased the amounts of the volatile metabolites 2-chloro-1,1,1-trifluoroethane and 2-chloro-1,1-difluoroethylene. SKF-525A also decreased the incidence and severity of hepatic damage. Both halothane (1%) and isoflurane (1.1%) anesthesia caused similar reductions in mean arterial blood pressure. However, in contrast to halothane, isoflurane was not hepatotoxic. The results indicate that liver necrosis is unlikely to be caused by anesthesia per se, but rather by hepatotoxic metabolites of halothane. This model offers the opportunity to study the pathogenesis of halothane hepatotoxicity after the administration of halothane alone.
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PMID:Guinea-pig model of halothane-associated hepatotoxicity in the absence of enzyme induction and hypoxia. 397 29


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