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)

Halothane (CF3CBrClH; H) biotransformation by cyt P-450 produces reactive intermediates along both oxidative (acyl chloride) and reductive (free radical) pathways that ultimately generate the metabolites trifluoroacetic acid and F-, respectively. Inhibiting oxidative metabolism with deuterated halothane (d-H) reduces resultant injury in our guinea pig model of acute H hepatoxicity. To elucidate whether covalent binding of reactive intermediates to proteins (oxidative pathway) or lipids (reductive pathway) is a mechanism of necrosis, male outbred Hartley guinea pigs (600-725 g), N = 8, were exposed to either 1% (v/v) H or d-H at either 40% or 10% O2 for 4 hr. One-half of the animals were killed immediately after exposure for binding studies; the remainder at 96 hr post for evaluation of hepatotoxicity. Covalent binding of halothane intermediates to liver protein or lipid was determined by measuring the fluoride content of the bound moieties. The use of d-H and/or 10% O2 during exposure led to 63-88% reductions (p less than 0.01) in plasma trifluoroacetic acid concentrations (H-40% O2 = 546; 73 mM, N = 8) which were accompanied by 33-60% decreases (p less than 0.01) in binding to liver proteins (H-40% O2 = 1.36; 0.26 nmoles bound F-/mg protein, N = 4), 78-84% decreases (p less than 0.05) in 48 hr plasma ALT levels (H-40% O2 = 308; 219, control = 23 + 3, N = 4) and a total amelioration of centilobular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Covalent binding of oxidative biotransformation reactive intermediates to protein influences halothane-associated hepatotoxicity in guinea pigs. 206 53

This study demonstrates that the exposure of phenobarbitone-treated rats to halothane at an oxygen concentration of either 10% or 14% results in marked decreases in cytochrome P-450 content and aminopyrine demethylase activity in animals sacrificed from 1 to 48 hr post-exposure. The alterations observed in the hepatic mixed function oxidase system were accompanied by increases in serum alanine aminotransferase (ALT), ornithine carbamyl transferase (OCT) and changes in liver pathology. However, the minor changes in cytochrome P-450 content and aminopyrine demethylase activity observed following exposure of enzyme-induced rats to halothane under normoxic conditions (i.e. 21% oxygen) were not of a sufficient magnitude to lead to hepatic cell necrosis. Halothane administration in the absence of phenobarbitone pretreatment (i.e. 21% oxygen) or during hypoxia alone (i.e. either 10% or 14% oxygen) did not result in any systematic changes in the parameters assayed. The results suggest that cytochrome P-450 may catalyse its own inactivation by virtue of greater free radical production under conditions which favour the non-oxygen dependent metabolism of halothane. The impairment in microsomal function as evidenced by decreases in cytochrome P-450 and aminopyrine demethylase activity are considered to occur as a primary consequence of the reductive metabolism of halothane. Data are presented which support the concept of the initiation of hepatic damage occurring during the period of anaesthesia with halothane.
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PMID:Changes in rat hepatic microsomal mixed function oxidase activity following exposure to halothane under various oxygen concentrations. 310 40

Rats were exposed to halothane vapour, 50 p.p.m., or air for a period of four weeks. Within each exposure group, some animals drank plain water, some received water plus phenobarbitone, while some received water plus isoniazid. Halothane exposure resulted in increased serum bromide concentrations and liver injury evidenced by increased serum alanine aminotransferase activity, focal hepatocellular necrosis and fatty change. Administration of isoniazid reduced halothane metabolism by 33% as assessed by serum bromide concentrations, and completely blocked the injurious effects of halothane on the liver, suggesting that halothane metabolism plays a role in halothane hepatotoxicity under these conditions. Administration of phenobarbitone partially prevented the increase in serum alanine aminotransferase activity and hepatocellular necrosis due to halothane. In contrast to isoniazid, phenobarbitone led to a slight increase in halothane metabolism. However, phenobarbitone also caused an increase in liver size, such that the amount of halothane metabolised per gram of liver was reduced by phenobarbitone treatment. These results suggest that metabolism of halothane is an important factor in liver injury due to prolonged, subanaesthetic halothane exposure.
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PMID:Effects of treatment with phenobarbitone or isoniazid on hepatotoxicity due to prolonged subanaesthetic halothane inhalation. 335 55

Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.
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PMID:Halothane hepatotoxicity in Fischer 344 rats pretreated with isoniazid. 356 16

Acetaminophen (Tylenol) is a widely used analgesic/antipyretic drug which is enzymatically bioactivated, or toxified, by the cytochromes P-450 to a hepatotoxic reactive intermediary metabolite. Brief general anesthesia with diethyl ether has been shown to inhibit both the toxifying cytochromes P-450 and enzymatic glucuronidation, the latter constituting up to 60% of acetaminophen elimination via a nontoxifying pathway. Thus ether potentially could produce a temporally differentiated inhibition of bioactivating and "detoxifying" pathways, resulting in an enhancement of acetaminophen hepatotoxicity if the balance favored bioactivation. To evaluate this possibility, separate groups of male NIH strain mice were treated with acetaminophen at different times after 5 min of anesthesia with ether. Ether produced a 40-fold enhancement in acetaminophen hepatotoxicity as determined by plasma glutamic-pyruvic transaminase (GPT) concentrations. This toxicologic enhancement was observed only if acetaminophen administration was delayed, with a maximal enhancement when acetaminophen was given 6 hr after ether, and no effect with a delay of 16 hr. Similar studies in male CD-1 mice were carried out using halothane (Fluothane) as the general anesthetic given either over 5 min or over 1 hr. While halothane given over 5 min had no effect, a 1 hr anesthetic duration produced a 10-fold increase in acetaminophen hepatotoxicity as determined by peak GPT concentration, with no observed hepatotoxicity in the halothane controls. Toxicologic enhancement occurred only with delayed administration of acetaminophen; however, the maximal enhancement observed with a 6-hr delay was still evident with a 12-hr delay. Conversely, inhibition of acetaminophen hepatotoxicity was observed if acetaminophen was given either 2 hr or 18 hr after halothane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Delayed enhancement of acetaminophen hepatotoxicity by general anesthesia using diethyl ether or halothane. 369 20

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

In phenobarbital (phenemalum NFN)-pretreated male rats exposed to 1% halothane for 2 hrs under hypoxic conditions (10% O2), significant increases in serum enzyme activities of alanine aminotransferase and sorbitol dehydrogenase were observed 24 and 48 hrs later indicating liver damage. In this known model of halothane hepatotoxicity, pretreatment with (+)-catechin (200 mg/kg orally) or silybine (150 mg/kg orally) protected against halothane-induced liver injury, whereas diethyldithiocarbamate (200 mg/kg orally) failed to be effective. Halothane decreased the concentration of reduced glutathione in liver only under hypoxic conditions indicating that glutathione might be involved in the non-oxidative metabolic pathways of halothane. Free fluoride in plasma was used as a measure of non-oxidative defluorination of halothane. Higher plasma fluoride levels were observed under conditions which led to hepatotoxicity but did not correlate with the protective effects of the antidotes. This further supports the assumption that 2-chloro-1,1,1-trifluoroethane might be the radical intermediate responsible for halothane hepatotoxicity.
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PMID:Influence of dithiocarb, (+)-catechin and silybine on halothane hepatotoxicity in the hypoxic rat model. 631 40

Fischer-344 rats of both sexes were exposed to halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) at a concentration of 50 p.p.m. for twelve weeks. During the course of the experiment, weight gain of both sexes was depressed and serum alanine aminotransferase activities were elevated, compared to control animals. The temporal pattern of alanine aminotransferase elevation differed between the sexes. After 12 weeks of exposure, liver/body weight ratio was increased in both sexes, and pathological changes were observed in their livers. Livers of all halothane-exposed animals showed focal liver cell necrosis, considerable lobular disarray and occasional mitoses. Many liver cells showed fatty change. None of these changes were observed in any control animals. These results indicate that prolonged exposure to a low concentration of halothane caused mild liver damage with regeneration. This finding may be of significance to humans occupationally exposed to halothane.
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PMID:Hepatic injury in rats due to prolonged sub-anaesthetic halothane exposure. 661 2

Exposure of hyperthyroid rats to halothane results in a centrilobular necrosis of the liver and an 11-fold increase in serum glutamate-pyruvate transaminase (SGPT) levels. These effects are not seen in euthyroid animals. Paradoxically, administration of diethylmaleate to hyperthyroid rats significantly decreased the levels of hepatic glutathione and blocked the halothane-induced hepatic necrosis as well as decreased the elevation of SGPT. In contrast, pretreatment of animals with N-acetylcysteine, an intracellular sulfhydryl repletor , significantly increased the severity of the halothane-induced hepatic necrosis and increased the elevation of SGPT. Similarly, cysteamine, another intracellular sulfhydryl repletor , also exacerbated halothane-induced liver injury. Halothane-induced hepatotoxicity is at least in part apparently regulated by cellular glutathione levels. Paradoxically, glutathione seems to be involved in the bioactivation rather than the detoxification of halothane.
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PMID:Paradoxical effects of perturbation of intracellular levels of glutathione on halothane-induced hepatotoxicity in hyperthyroid rats. 672 95

Halothane hepatotoxicity was observed after exposing hyperthyroid rats to 0.625% halothane for 4 hr under hypoxic conditions (10% O2). In this model, increases in serum enzyme activities of the alanine aminotransferase (GPT) and the sorbitol dehydrogenase (SDH) were evident immediately following exposure and were six-fold higher than in the phenobarbital-hypoxic model. Plasma free-fluoride levels estimated immediately after exposure to halothane were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as were increased twofold in halothane-exposed hyperthyroid rats under hypoxic conditions as compared to a sixfold increase in the phenobarbital-hypoxic model. The concentration of glutathione in liver was more markedly decreased in hyperthyroid rats than in phenobarbital-induced rats. The fact that no clear-cut correlation was found between defluorination and hepatotoxicity in both models may favor the hypothesis that a non-defluorinated metabolite of halothane, e.g., 2-chloro-1,1,1-trifluoroethyl radical, is the reactive intermediate responsible for the liver lesions. On the other hand, intracellular hypoxia due to hypermetabolism during the hyperthyroid state may be the reason for the higher sensitivity of hyperthyroid rats.
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PMID:Halothane hepatotoxicity in hyperthyroid rats as compared to the phenobarbital-hypoxia model. 686 87


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