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)

Tissue slices were used to compare relative peroxidation capacity of bromotrichloromethane (BrCCl3) and t-butyl hydroperoxide (BHP) by measurement of both peroxidation products and biochemical indices of damage. In liver and testes slices, BHP increased thiobarbituric acid reactive-substances (TBARS) and total aldehydes, measured as cyclohexanedione-reactive substances (CHDRS), to a greater extent than did an equimolar amount of BrCCl3. GSH was decreased more by BHP than by BrCCl3. Neither compound released lactate dehydrogenase or glutamic-pyruvic transaminase from liver slices. Treatment of rats with cyanamide, an aldehyde dehydrogenase inhibitor, increased the total CHDRS in liver slices and medium after incubation with BHP or BrCCl3. HPLC of the CHDRS showed hexanal and propanal increased to the greatest extent. The hydroperoxide, BHP, which does not require metabolism to an active species, was a better initiator of peroxidation than the halogenated hydrocarbon, BrCCl3, which must be metabolized to a radical species before it can initiate peroxidation.
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PMID:Halogenated hydrocarbon and hydroperoxide-induced peroxidation in rat tissue slices. 377 41

Time- and dose-dependent correlations of monochlorobenzene (CB) hepatotoxic effects were studied in view of (1) assumed mechanistic similarities to bromobenzene (BB), (2) the paucity of these data for CB, and (3) the relatively greater environmental importance of CB compared with BB. An ip dosage of 9.8 mmol/kg CB (approximately equal to LD10) produced evidence of liver toxicity over a 72-hr time course. Sulfobromophthalein (BSP) retention was maximized 3-16 hr post-treatment and normalized after 72 hr, whereas plasma alanine aminotransferase activity (ALT) and morphological evidence of damage were maximized about 48 hr after dosing. Maximal covalent binding to liver protein (3.07 nmol/mg) had occurred by 24 hr and approximately 36% of the administered dose had appeared in the urine by 48 hr. Liver and plasma CB concentrations were proportionally increased over the dosage range 2.0-14.7 mmol/kg but marked centrolobular necrosis and ALT elevations were seen only at the two highest dosages (9.8 and 14.7 mmol/kg). On the other hand, all doses depressed hepatic glutathione (GSH) to between 30 and 40% of control by 4 hr. Evidence of rapid recovery was evident at 2.0 and 4.9 mmol/kg but GSH levels remained low through 8 hr after 9.8 or 14.7 mmol/kg. Liver/body weight ratios were increased to a similar extent at all dosages when measured 24 hr post-treatment. Urinary excretion ranged from 59% at the low dosage to only 19% at the highest dosage by 24 hr. Dose-related covalent binding to liver protein at 24 hr occurred up to 9.8 mmol/kg but the binding associated with 14.7 mmol/kg was equivalent to that seen with the 4.9 mmol/kg dosage (1.6 nmol/mg protein). Cytochrome P-450 levels were depressed to between 50 and 80% of control 24 hr post-treatment with no clear dose relationship. While the hepatotoxic effects of CB and BB appear similar, these data suggest that some mechanistic differences are involved.
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PMID:Temporal and dose-response features of monochlorobenzene hepatotoxicity in rats. 398 88

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

When male Sprague-Dawley rats were treated with sodium selenite (1 mg/kg, sc) 24 hr prior to or simultaneously with bromobenzene (2.5 mmol/kg, ip) and sacrificed 48 hr after the bromobenzene dose, increased levels of the activities of serum transaminases (serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) induced in the bromobenzene-treated rats were significantly reduced in the presence of selenium. However, no such reduction in the transaminases activities were observed when rats were either pretreated with selenite for 48 hr or pretreated with 0.1, 0.2, or 0.5 mg/kg of selenite. Although selenium alone had no effect on the hepatic microsomal drug metabolism, simultaneous treatment of selenite (1 mg/kg) with bromobenzene resulted only an increase in the activity of aniline hydroxylase after 48 hr as compared to that in the bromobenzene-treated group. When rats were given 2.5, 10, and 20 ppm of selenite in drinking water daily for 4 weeks prior to an ip injection of 2.5 mmol/kg of bromobenzene and were sacrificed 48 hr after bromobenzene administration, a reduction in the SGOT activities in all the pretreated groups and a reduction of SGPT activity in 20 ppm selenite-treated group were observed when compared with those in the bromobenzene-treated groups. A dose-dependent increase in hepatic GSH concentrations were observed due to such chronic selenium treatment. Treatment with selenite (1 mg/kg) 24 hr prior to bromobenzene injection (2.5 mmol/kg) increased initially both o and p-bromophenols in the rat urine at 0-7.5 hr without affecting urinary thioethers. On the contrary, the ratio of thioethers to p-bromophenol was significantly higher in both 2.5 and 10 ppm selenite-pretreated (4 weeks) rats as well as a significant increase in the ratio of thioethers to total phenolic metabolites in 10 ppm and an increase close to significant in 2.5 ppm selenite-treated rats were observed initially at 0-7.5 hr urine samples. These results indicate that acute selenium pretreatment under certain conditions, favors increased hydroxylation of the intermediate bromobenzene epoxides, whereas higher detoxification of the epoxides involving hepatic glutathione (GSH)/GSH transferases pathway is more favored due to increased biosynthesis of GSH in certain chronic selenium treated rats.
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PMID:Influence of selenium on the metabolism of bromobenzene and a possible relationship to its hepatotoxicity. 401 88

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

Single injections of epinephrine significantly lowered the hepatocellular levels of reduced glutathione (GSH) while producing small but significant elevations in serum glutamic-pyruvic transaminase (SGPT) activity. Hormones, i.e. glucagon and the corticosteroids, were also found to depress significantly hepatic glutathione. Based upon the agonist-antagonist studies performed, the hepatic GSH lowering effects of epinephrine appear to be mediated solely by alpha 2 receptors. Adrenergic antagonists with alpha 2 receptor blocking properties, phenotolamine and yohimbine, prevented the epinephrine-induced lowering of GSH while agonists with alpha 2 activity, clonidine and guanabenz, mimicked epinephrine's response. Antagonists with either alpha 1 or beta activity, i.e. prazosin, phenoxybenzamine and propranolol, did not prevent the epinephrine-induced lowering of hepatic GSH. Contrary to these findings antagonists with either alpha or beta receptor blocking activity significantly reduced the epinephrine-induced elevations in SGPT activity. Thus, there was no apparent relationship between the elevation of SGPT activity and the reduction in hepatic glutathione levels. It is concluded that the therapeutic administration of these compounds, or physiologic responses to stress or pain, may exacerbate the hepatotoxicity of compounds detoxified by GSH or alter important glutathione-mediated hepatocellullar processes.
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PMID:The perturbation of hepatic glutathione by alpha 2-adrenergic agonists. 613 90

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

Severity of liver damage 24 hr after i.p. administration of carbon tetrachloride (0.2 ml/kg), allyl alcohol (0.036 ml/kg) or galactosamine (400 mg/kg) was evaluated in male rats at 4-5, 14-15 or 24-25 months of age. Allyl alcohol hepatotoxicity, as judged by light microscopy and serum alanine aminotransferase levels, increased markedly as a function of age. In contrast, carbon tetrachloride and galactosamine toxicities were unchanged or slightly diminished in old rats. Hepatic glutathione (GSH) concentrations were unaffected by aging; thus, the age-dependent increase in susceptibility to allyl alcohol toxicity was not a result of diminished GSH availability in old age. Hepatotoxicant-induced changes in GSH were observed in allyl alcohol-treated old rats (20% increase) and in galactosamine-treated young-adult and middle-aged rats (30% decrease).
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PMID:Effect of aging on liver glutathione levels and hepatocellular injury from carbon tetrachloride, allyl alcohol or galactosamine. 653 34

A total of 96 crossbred pigs received various levels of sodium selenite to determine the effect of dietary selenium (Se) on growing swine fed corn-soybean meal diets. Levels of supplemental Se were 0, 4, 8, 12, 16 and 20 micrograms/g. There were linear decreases (P less than .01) in both gain and feed intake with increasing levels of dietary Se. Feed/gain increased numerically as dietary Se increased. Hair Se increased quadratically (P less than .01) and blood Se increased linearly (P less than .01) with increasing level of dietary Se. Cell volume and hemoglobin were not affected by dietary treatment. Increasing dietary Se significantly increased glutathione peroxidase (GSH-Px), glutamic-oxalacetic transaminase (GOT). and glutamic-pyruvic transaminase (GPT). External signs of selenosis were noted in some pigs fed 12 or 20 micrograms/g of Se. The toxic level of Se in a corn-soybean meal diet for crossbred pigs appears to be between 4 and 8 micrograms/g. Of variables studied, growth rate was the most sensitive indicator of chronic selenosis in swine.
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PMID:Toxic effects of selenium on growing swine fed corn-soybean meal diets. 654 46

The mechanisms underlying iodobenzene hepatotoxicity were investigated in Albino mice in which the hepatic glutathione (GSH) content had been decreased by nearly 50% by starvation for 16 h before poisoning. After iodobenzene administration (9 mmol/Kg, p.o.) the hepatic GSH content decreased progressively and liver necrosis, as measured by the plasma transaminase (GPT, GOT) levels, occurred in many animals at 12 and 16 h. A clear cut necrosis was evident only when the hepatic GSH depletion reached a threshold value (3.5-2.5 nmol/mg protein). The same threshold value was evident for the occurrence of lipid peroxidation (measured as both carbonyl functions and conjugated dienes in liver phospholipids). The highly significant correlation found between lipid peroxidation and liver necrosis supports the possibility of a cause-effect relationship between the two phenomena.
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PMID:[Depletion of liver glutathione induced by iodobenzene poisoning and its relation to lipid peroxidation and necrosis]. 666 14


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