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)

This study was done to determine the relationship between microsomal lipid peroxidation during hepatic ischemia/reperfusion and alteration in cytochrome P-450-dependent drug metabolism. Rats were pretreated with alpha-tocopherol to inhibit lipid peroxidation or with vehicle (soybean oil) and then subjected to 60 min no-flow hepatic ischemia in vivo. Control animals were time-matched sham-ischemic animals. After 1, 5 or 24 hr of reperfusion, liver microsomes were isolated and cytochrome P-450 and mixed function oxidases were studied. In vehicle-treated ischemic rats, serum ALT levels peaked at 5 hr (5,242 +/- 682 U/L) and were significantly reduced by alpha-tocopherol pretreatment (1,854 +/- 229 U/L, p less than 0.01). Similarly, microsomal lipid peroxidation was elevated in the vehicle-treated ischemic group, but this elevation was prevented by alpha-tocopherol pretreatment. Microsomal cytochrome P-450 content and aminopyrine-N-demethylase activity were both decreased in vehicle-treated ischemic rats to 60% and 70% of sham-ischemic control levels, respectively. Although alpha-tocopherol restored cytochrome P-450 content to the level of sham-ischemic control rats, aminopyrine-N-demethylase activity remained at 76% of control with alpha-tocopherol treatment (p less than 0.01 compared with sham-ischemic control). In contrast to what was seen with cytochrome P-450 and aminopyrine-N-demethylase, aniline p-hydroxylase activity was elevated in the vehicle-treated ischemic rats compared with sham-ischemic control rats. These increases were prevented by alpha-tocopherol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of alpha-tocopherol on hepatic mixed function oxidases in hepatic ischemia/reperfusion. 173 30

The pulmonary biochemical response, particularly the effects on mixed-function oxidases, was investigated in rats exposed to 40 ppm furfural for 1 h daily, 5 days per week, for periods of 7, 15 and 30 days. This concentration is ca. 22% of the acute LC50 dose. Exposure to furfural increased the activities of acid and alkaline phosphatases and glutamic-pyruvic transaminase, inhibited the activities of arginase and succinic dehydrogenases and elevated the concentration of lactic acid in the lungs. In the group of mixed-function oxidases, the activities of aminopyrene-N-demethylase and aniline hydroxylase (phase I, cytochrome P-450b specific) significantly increased and the activity of Benzo[a]pyrene hydroxylase (phase I, cytochrome P-450c specific) decreased. The activity of glutathione-S-transferase (phase II component) also was increased concurrently with a decrease in the concentration of glutathione. The magnitude of biochemical alterations in most cases was related directly to the duration of exposure. Our observations indicate that furfural caused pulmonary irritation, parenchymal injury and the regenerative proliferation of type II pneumocytes. Selective (cellular and/or cytochrome P-450 isozyme specific) enhancement of pulmonary mixed-function oxidases by furfural appears to stimulate its own pulmonary biotransformation, and the excretion of oxidative metabolites was facilitated by their enzymatic conjugation with glutathione.
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PMID:Inhalation toxicity of furfural vapours: an assessment of biochemical response in rat lungs. 178 39

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

The hepatotoxicity of paracetamol in mice of 2, 3, 8-10, 24-26, 32-34, and 52-54 wk of age was determined by lethality data, histopathologic examination of the liver, and appearance of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase activities in the plasma over an 8-h exposure period. At a dose of 300 mg/kg, there was evidence of hepatocytic necrosis and transaminase leakage in the 32- to 34- and 52- to 54-wk-old mice, but lethality was only recorded in the oldest age group. At 500 mg/kg, paracetamol produced 30% lethality in 3-wk-old mice and between 50 and 90% lethality in the adult age groups. There was histologic evidence of hepatocytic necrosis at all of these ages and its extent increased with age. Similarly, there were increases in plasma transaminases in each of these age groups. However, in 2-wk-old mice there was no lethality, no hepatocytic necrosis, and no increase in plasma transaminases. The lack of susceptibility of 2-wk-old mice to paracetamol toxicity was not due to immaturity of the cytochrome P-450 enzymes responsible for metabolism of paracetamol to its reactive metabolite (N-acetyl-p-benzoquinone imine). In fact, the activity of this enzyme pathway in 2-wk-old mice was greater than that in adults. The partial clearance of the glutathione-derived metabolites of paracetamol after a nontoxic (50 mg/kg) dose was 80% greater in 2-wk-old mice than in 8- to 10-wk-old mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postnatal mice have low susceptibility to paracetamol toxicity. 189 54

Hepatotoxicity of diethyldithiocarbamate (DDC) was investigated in rats. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were markedly elevated 24 hr after subcutaneous administration of DDC and histologically, the liver showed submassive necrosis. A sustained inhibition in the liver of Cu,Zn-superoxide dismutase (Cu-SOD) activity was observed following DDC treatment. DDC produced a significant loss in liver reduced glutathione (GSH) level after 1 hr, but the nadir was observed later than that of Cu-SOD. Catalase activity decreased gradually from 7 hr. Thiobarbituric acid reactive substances (TBARS) in the liver were significantly increased from 15 hr. Hepatic haemodynamics were scarcely changed up to 15 hr. Desferrioxamine (a chelator of iron) and piperonyl butoxide (an inhibitor of cytochrome P-450) prevented DDC-induced increases of both ALT and TBARS, but GSH did not, DDC hepatotoxicity was not changed by phenobarbital induction. Thus, we have shown that subcutaneous dose of DDC caused hepatotoxicity in rats. Although the exact sequence of its hepatotoxic factors is unproven, it seems likely that lipid peroxidation through the dysfunction of antioxidant defence factors and a toxic metabolite contribute to the formation of this liver injury.
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PMID:Hepatotoxicity of diethyldithiocarbamate in rats. 196 45

Due to the ubiquitous presence of p-xylene in air and the existing uncertainty regarding its hepatotoxic potential, we examined the effect of acute and short-term exposure to inhaled p-xylene on the liver. Male F-344 rats were exposed to 0 or to 1600 ppm p-xylene, 6 h/d, for 1 or 3 d. Exposure to inhaled p-xylene caused no histopathological evidence of hepatic damage and had little or no effect on the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, ornithine carbamyl transferase, alkaline phosphatase, and total bilirubin. Exposure to p-xylene for 1 or 3 d resulted in an increase in relative liver weight on d 1 post-exposure. The concentration of hepatic cytochrome P-450 was increased by both p-xylene exposure regimens on d 1 postexposure and had returned to control levels by d 3 following the single p-xylene exposure and by d 2 following the 3-d exposure. These observations provide consistent evidence that acute and short-term exposure to 1600 ppm p-xylene by inhalation did not produce overt hepatotoxicity but resulted in a significant increase in the concentration of hepatic cytochrome P-450, the principal enzyme system involved in the metabolic biotransformation of xenobiotics.
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PMID:Assessment of the hepatotoxicity of acute and short-term exposure to inhaled p-xylene in F-344 rats. 200 13

The antihepatotoxic properties of uridine-diphosphoglucose (UDPG, Toxepasi) have been evaluated in a well-established model of liver damage, the liver fluke infection (experimental fascioliasis in the rat), which causes a dramatic loss of the microsomal drug-metabolizing monooxygenase (MFO) and glucuronosyltransferase (GT) enzyme systems as a consequence of peroxidative damage to microsomal membrane lipids. Administration of 100 mg/kg UDPG i.p. to the infested rat for the entire course of the infection (40 days) positively affects the parameters reflecting the integrity of the liver cell (serum glutamate-pyruvate, GPT and glutamate-oxaloacetate, GOT, transaminases) and the detoxifying capacity of the liver (cytochrome P-450, cytochrome b5, cytochrome P-450-dependent p-nitroanisole O-demethylase and aniline hydroxylase activities, and the p-nitrophenol glucuronidation) and greatly reduces the lipid peroxidative phenomen in membranes from whole liver (tissue malonic dialdehyde content) and in membranes of the microsomal fraction (conjugated diene absorption). As a consequence of this, the total lipid and phospholipid contents of the liver are restored, there is minimal loss of latency of GT enzyme(s), cytochrome P-450 conversion to cytochrome P-420 is fairly negligible and total liver glutathione content is also restored. Therefore, UDPG restores liver function by protecting the endoplasmic reticulum membranes from the oxidative stress resulting from activation of the CN-insensitive respiratory burst of the phagocytic cells consequent to Fasciola hepatica invasion, migration and growth. It is very likely that UDPG acts as an effective antilipoperoxidative agent through both direct (as demonstrated by our in vitro experiments) and indirect mechanisms (stimulation of the glycolytic pathway, and hence of the reducing equivalents----glutathione----vitamin E supply).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antihepatotoxic properties of uridine-diphosphoglucose in liver fluke infection. Experimental fascioliasis in the rat. 211 87

Cocaine has been associated with hepatotoxicities in man and is a potent hepatotoxin in mice. The theorized toxic metabolite of cocaine is thought to be generated by a multistep pathway mediated primarily by cytochrome P-450. Ethanol, whether administered acutely or chronically, is known to have diverse effects on numerous hepatocellular biochemical pathways. The present study was designed to characterize not only the effects of acute and chronic ethanol on cocaine-mediated hepatotoxicity but also on the hepatic reduced glutathione (GSH) in an attempt to correlate depletions of GSH with changes in toxicity. Male and female mice were administered an acute 50 mg/kg dose of cocaine either 1 hr after an acute 3 g/kg dose of ethanol, or after 5 days of consuming an ethanol-containing liquid diet. Serum alanine aminotransferase (ALT) activity was measured in blood collected 24 hr after the acute cocaine dose. In addition, hepatic reduced glutathione (GSH) and cytochrome P-450 content were measured at the point in the pretreatment where cocaine was administered. The results of this study indicate that both acute and chronic ethanol pretreatment can markedly enhance the hepatotoxicity of cocaine in both male and female mice and that the enhancement is significantly greater after chronic ethanol pretreatment. Hepatic GSH was slightly decreased 1 hr after an acute dose of ethanol and significantly decreased after chronic ethanol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potentiation of cocaine-mediated hepatotoxicity by acute and chronic ethanol. 217 68

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

Hepatic ischemia induced in vivo by ligation of the left hepatic lobe of rats for up to 2 hr had no effect on cytochrome P-450, cytochrome c reductase, or lobe histology; however, cytochrome b5 increased with ischemia duration. Ethylmorphine demethylation decreased 35% after 2 hr of ischemia. Reperfusion of tissue previously made ischemic for up to 2 hr was associated with appreciable necrosis as well as decreases in cytochrome P-450, cytochrome b5, cytochrome c reductase, and ethylmorphine demethylation. Serum alanine transaminase and aspartate transaminase concentrations were increased by reperfusion of previously ischemic tissue. Reperfusion of the previously ischemic lobe for 18 hr was associated with a greater loss of cytochromes P-450 and b5, cytochrome c reductase, and ethylmorphine demethylation than reperfusion for 1 hr. The total decrease in cytochrome P-450 and b5 content was equal to the decrease in total microsomal heme content, although cytochrome P-450 decreased more than cytochrome b5. Ethoxyresorufin deethylation by hepatic microsomes from 3-methylcholanthrene-treated rats was decreased by ischemia-reperfusion; however, pentoxyresorufin dealkylation by hepatic microsomes from phenobarbital-treated rats was not, suggesting specific cytochrome P-450 isozyme loss. In vitro NADPH-dependent lipid peroxidation in hepatic microsomes from control and phenobarbital- and 3-methylcholanthrene-treated rats resulted in a selective decrease of ethoxyresorufin but not pentoxyresorufin dealkylation, similar to that observed in livers subjected to ischemia-reperfusion in vivo. These data suggest that cytochrome P-450, ethylmorphine demethylation, and ethoxyresorufin deethylation are more susceptible to ischemia-reperfusion injury than cytochrome b5 or pentoxyresorufin dealkylation.
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PMID:Effects of hepatic ischemia-reperfusion injury on the hepatic mixed function oxidase system in rats. 225 Jun 63


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