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 interaction of ethanol and aflatoxin B1 (AFB1)-induced hepatotoxicity was studied in male Wistar rats using the activity of plasma GOT and GPT, liver triglyceride and histopathologic changes of liver necrosis as indices. Pretreatment of four oral doses of ethanol (4.0 g/kg BW each) at 48, 45, 24 and 21 hrs prior to AFB1 (0.5 to 2.0 mg/kg BW) single i.p. administration caused a significant increase in the activity of PGOT (6 folds) and PGPT (5 folds), liver triglycerides (2 folds) and severity of liver necrosis at 48 hrs after AFB1 administration. Ethanol pretreatment potentiated AFB1-induced hepatotoxicity by increasing MFO enzymes, aniline hydroxylase and p-nitroanisole-O-demethylase activity and lipid peroxidation, and decreasing in cytochrome b5, epoxide hydrolase activity and hepatic glutathione content. However, it did not cause any significant change in the activity of NADPH-cytochrome c reductase and glutathione-S-transferase and cytochrome P-450. These results suggest that potentiation of ethanol pretreatment on AFB1-induced hepatotoxicity may be due to an increase in the metabolic formation of AFB1-2, 3-oxide and subsequent binding to DNA.
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PMID:Potentiation of aflatoxin B1 induced hepatotoxicity in male Wistar rats with ethanol pretreatment. 308 65

The hepatotoxicity of chloroform (CHCl3) is thought to require biotransformation, by the polysubstrate monooxygenase system (P-450), to a reactive intermediate(s). Therefore, the potentiation of CHCl3-induced hepatotoxicity, which occurs following exposure to certain ketones, may hypothetically be explained by a reduced capacity of the cell to form glutathione conjugates (detoxicate the intermediate) and (or) by an increased rate of reactive intermediate(s) generation secondary to a modification of the P-450 system. To test these hypotheses, liver damage, as indicated by elevation in plasma alanine aminotransferase and ornithine carbamyl transferase activities, was modulated in male Sprague-Dawley rats by varying the time interval (10, 18, 24, 48, 72, 96 h) between acetone, 2-butanone, or 2-hexanone (15 mmol/kg, p.o.) pretreatment and CHCl3 (0.5 mL/kg, p.o.) administration. These data were compared with hepatic glutathione and with various parameters of the polysubstrate monooxygenase system: cytochrome P-450, cytochrome c reductase, cytochrome b5, and microsomal binding of 14CHCl3-derived radiolabel. Reduced detoxication capacity does not appear to be involved as hepatic glutathione levels were not reduced. Globally, a relationship between modifications to the polysubstrate monooxygenase system and potentiation of CHCl3-induced hepatotoxicity appears to exist. The rank order of each ketone's ability to modify P-450 parameters was the same in most instances as that based on peak ability to potentiate CHCl3-induced hepatotoxicity: 2-hexanone greater than 2-butanone greater than or equal to acetone. Therefore, these results suggest that a general relationship exists between the ketone-induced potentiation of CHCl3-induced hepatotoxicity and increased CHCl3 reactive metabolite generation. However, other factors may also contribute to the phenomenon.
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PMID:The role of biotransformation-detoxication in acetone-, 2-butanone-, and 2-hexanone-potentiated chloroform-induced hepatotoxicity. 344 91

Weanling, male Sprague-Dawley rats given 10% ethanol in the drinking water and food ad lib. for up to 8 weeks consumed 17% of their calories as ethanol. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver histology by light microscopy were unaffected by this treatment. Similarly, hepatic microsomal NADPH-cytochrome c reductase, ethylmorphine N-demethylase and benzphetamine N-demethylase activities were also not affected by ethanol consumption. On the other hand, cytochrome P-450 content, aniline hydroxylase activity and acetaminophen metabolism as measured by both the cysteine conjugate and the [3H]acetaminophen covalently-bound to microsomal protein were increased significantly by ethanol consumption. The maximal effect was seen by 6 weeks. The 2- to 3-fold increase in aniline and acetaminophen metabolism, the absence of liver damage, and the similarity in weight gains and caloric intakes for controls and treated animals suggest that the rat on 10% ethanol in the drinking water is a reasonable model for studies of the effect of moderate alcohol consumption on specific biochemical pathways.
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PMID:Studies on the effect of chronic consumption of moderate amounts of ethanol on male rat hepatic microsomal drug-metabolizing activity. 393 44

To explore a possible relationship between metabolism and lethality, the acute toxicity of naturally occurring perilla ketone (PK), 1-(3-furyl)-4-methyl-pentan-1-one, was examined in the uninduced mouse, hamster, rabbit, dog and pig. The LD50 (+/- SE), determined using intraperitoneal (ip) injection, for the mouse and hamster were low at 5.0 +/- .3 and 13.7 +/- .9 mg/kg, respectively. The rabbit died from an ip dosage of near 14 mg/kg and estimated ip LD50 dosages were quite high for the dog and pig, being 106 +/- 25 mg/kg and over 158 mg/kg, respectively. Dogs and the pig that died from ip injections of PK displayed varying degrees of midzonal and centrilobular liver damage and dogs also had elevated serum alkaline phosphatase and glutamic-pyruvic transaminase activities. In contrast, rodents and rabbits display only pulmonary toxicity from this agent. Cytochromes P-450 and b5 concentrations and NADPH-cytochrome c reductase activity were determined for the lung, liver and kidney of mice, hamsters, rabbits, dogs, swine, sheep and cattle. High correlation between lethality and enzyme concentration further supports the hypothesis that enzymatic bioactivation of PK is required for toxicity in all species.
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PMID:Species susceptibility to the pulmonary toxicity of 3-furyl isoamyl ketone (perilla ketone): in vivo support for involvement of the lung monooxygenase system. 397 46

Experiments were conducted to examine the role of zinc in the prevention of bromobenzene hepatoxicity in male rats. Bromobenzene (BB) (7.5 mmol/kg, ip) produced a marked hepatotoxicity as evidenced by increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and a marked depression in hepatic glutathione (GSH) content 24 hr after administration. The administration of zinc (92 mumol Zn/kg, ip, at 48 and 24 hr prior to the bromobenzene) ameliorated the bromobenzene elevations in plasma AST (25%) and plasma ALT (50%) but did not alter the decreases in hepatic GSH. Following administration of [14C]BB, the radioactive label was distributed primarily in the cytosolic and lipid fractions derived from liver homogenates. Furthermore, the subcellular distribution of [14C]BB was not altered by zinc pretreatment. The extent of covalent binding of [14C]BB metabolites to hepatic tissue was significantly depressed in zinc-treated rats. Zinc induced the hepatic levels of metallothionein but [14C]BB did not bind to this sulfhydryl rich protein. Further experiments showed that zinc treatment depressed cytochrome P-450 content, the activity of NADPH cytochrome c reductase, and the metabolism of aniline, but not that of ethylmorphine. These studies suggest that the hepatoprotective effect of zinc against bromobenzene toxicity does not involve altered binding of the reactive toxic metabolite to glutathione or metallothionein, but it may be mediated by the inhibitory effect of zinc on the microsomal cytochrome P-450-dependent drug metabolizing system.
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PMID:Amelioration of bromobenzene hepatotoxicity in the male rat by zinc. 398

Male Wistar rats were exposed (six hours/day, five days/week) to 0, 50, 300 or 600 p.p.m. of ethylbenzene vapour in the air, and killed after 2, 5, 9 or 16 weeks of exposure. After 600 p.p.m., liver-microsomal protein but not cytochrome P-450 concn. was slightly increased; NADPH-cytochrome c reductase was increased maximally by 30% (1.3-fold), 7-ethoxycoumarin O-deethylase (1.8-fold) and UDPG-transferase (2.3-fold). The increase in liver-cytosolic D-glucuronolactone dehydrogenase paralleled the glucuronidation activity (less than or equal to 2-fold). In the kidneys, only 7-ethoxycoumarin O-deethylase (less than or equal to 3.5-fold) and UDPG-transferase (less than or equal to 1.8-fold) showed dose-related increases. Ethylbenzene exposure did not deplete hepatic glutathione (GSH); kidney GSH was slightly increased (less than or equal to 1.3-fold) according to dose. Urine excretion of thioethers was increased with dose, and at 600 p.p.m. was eight times control levels. At 600 p.p.m. there was no increase in serum alanine aminotransferase activity, and liver cells showed slight proliferation of smooth endoplasmic reticulum, slight degranulation and splitting of rough endoplasmic reticulum and enlarged mitochondria, but no necrosis.
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PMID:Biochemical and morphological effects of long-term inhalation exposure of rats to ethylbenzene. 402 64

Male Wistar rats received methyl methacrylate monomer (MMA) i.p. in olive oil 1.0 g/kg body weight on 3 successive days. The weight of the livers and kidneys, and the body weights did not differ from their controls. On the fifth day after treatment, hepatic NADPH-cytochrome c reductase, 7-ethoxycoumarin 0-deethylase and the 2,5-diphenyloxazole hydroxylase exhibited maximal decreases in activity (25%, 58%, 36%, respectively) without any coincident effect on the total amount of cytochrome P-450 hemoprotein itself. One week later these activities had returned to control levels. The enzymatic changes in the kidneys were smaller in magnitude, and they were also reversed sooner. A single i.p. dose of MMA (2 g/kg body weight) caused elevation of serum alanine aminotransferase activity. A tenfold increase of the excretion rate of urinary thioethers was also discovered. The hepatic reduced glutathione (GSH) was depleted in 3 h to 20% and the GSSG to half of the value in controls. In kidneys, the GSH was decreased to 48% in 3 h before an apparent phase of overrecovery. At the end of the 24 h observation period, cytochrome P-450 concentrations were somewhat decreased in the liver. The GSH contents showed dose and time-dependent reversible decreases in isolated hepatocytes when incubated for 2 h in a medium containing MMA at the nominal concentrations of 0, 2, 5, or 10 mM. None of the treatments affected either the content of cytochrome P-450 or the viability of the liver cells.
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PMID:Effects of methyl methacrylate on non-protein thiols and drug metabolizing enzymes in rat liver and kidneys. 640 23

Acute or chronic treatment of rats with isopropanol caused a significant increase in hepatic cytochrome P-450 content and a two- to threefold increase in aniline hydroxylase and 7-ethoxycoumarin O-deethylase activities, but no significant change in ethylmorphine N-demethylase or benzo(a)pyrene hydroxylase activity. In rats treated with isopropanol and challenged with CCl4, liver toxicity of CCl4 was characteristically potentiated, as assessed by elevation of serum glutamic-pyruvic transaminase (SGPT) levels. Isopropanol pretreatment also potentiated CCl4-induced damage to the hepatic monooxygenase system. In addition to a decrease in cytochrome P-450, rats treated with isopropanol and challenged with CCl4 showed a nonspecific decrease not only in aniline hydroxylase and 7-ethoxycoumarin O-deethylase activities, but also in ethylmorphine N-demethylase, benzo(a)pyrene hydroxylase, and NADPH-cytochrome c reductase activities. These results were confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of solubilized microsomes. The electrophoretic results showed that isopropanol pretreatment markedly potentiated the CCl4-caused destruction of cytochrome P-450 hemeproteins. The data strongly suggest that isopropanol increases one or more forms of cytochrome P-450 which selectively enhance the metabolism of CCl4 to an active metabolite. This active metabolite then causes a nonselective damage to the microsomal mixed-function oxidase system.
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PMID:Isopropanol enhancement of cytochrome P-450-dependent monooxygenase activities and its effects on carbon tetrachloride intoxication. 663 85

The toxic effects of paraquat administered to rats in drinking water for a period of 30 days were studied. Paraquat had no effect on the body weight gain or on organ weights of rats. However, microsomal NADPH-cytochrome c reductase activity and cytochrome P-450 content were increased in rats given paraquat in drinking water. The obtained differences were statistically significant. Serum alkaline phosphatase activity was not significantly changed with respect to control animals but a statistically changed, with respect to control animals, statistically significant decrease was established in serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activity of test animals compared to values obtained for control groups. Hematological data showed that paraquat caused a decrease in hemoglobin concentration and total red blood cell number, while the total white blood cell number was significantly increased compared to values obtained for control animals.
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PMID:Subacute toxicity of paraquat in rats--biochemical effects. 664 84

In the present study we first demonstrated that T-2 toxin markedly stimulated lipid peroxidation specifically in the liver of rats. The amount of lipid peroxides in the liver, estimated by the thiobarbituric acid (TBA) method, increased dose dependently, being proportional to the extent of its acute toxicity measured by various parameters in rats fed a commercial diet. Further, to elucidate the mechanism of lipid peroxidation and its role in hepatic injury caused by T-2 toxin, time-course studies on the correlation between lipid peroxide content and some biological and histopathological data were undertaken in rats given 4 mg of the toxin/kg perorally. The TBA reactive substances in the liver began to increase after 6 hr. However, much earlier than this there were some other alterations, which included decreases in the amount of cytochrome P-450 in the liver, of GPT (thereafter an increase) and phospholipids in the plasma, and of basophilic masses in the hepatocytes (arrayed as a rough endoplasmic reticulum in the electron micrograph). The vitamin E-deficient study showed that vitamin E markedly inhibited the stimulative effect of T-2 toxin on lipid peroxidation, but not diminish any other measured parameters of the injury. The toxin-induced stimulation of lipid peroxidation does not appear to be caused by activation of microsomal NADPH-cytochrome c reductase nor by a decrease in the level of cytosolic glutathione peroxidase. These results suggest that T-2 toxin might induce some alteration of the membrane structure and consequently might stimulate lipid peroxidation in situ.
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PMID:Elevation of thiobarbituric acid values in the rat liver intoxicated by T-2 toxin. 672 68


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