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)

Experimental models for halothane hepatotoxicity require microsomal enzyme induction by phenobarbital or triiodo-thyronine pretreatment and hypoxic conditions. The role of GSH in the metabolism of halothane, however, is still unclear. We therefore pretreated male rats with phorone to deplete hepatic GSH, phenobarbital as a microsomal enzyme inducer and exposed them to halothane 1% for 4 h under hypoxia (10% O2). Increases in serum enzyme activities of alanine aminotransferase (GPT) and sorbitol dehydrogenase (SDH) were observed 24 and 48 h later. Histomorphological examinations showed centrilobular hepatic necrosis. In GSH-depleted rats the increments of serum enzyme activities and histomorphological alterations were significantly aggravated as compared with controls. In this model (+)-catechin protected against halothane-induced hepatotoxicity as evidenced by reduced serum enzyme elevations and morphological alterations whereas diethyldithiocarbamate failed to exert any protective effects. Free fluoride concentrations in plasma was used as an index of the non-oxidative defluorination of halothane. Increased plasma fluoride levels were observed under conditions which evoked hepatotoxicity but did not correlate with the protective effect of (+)-catechin. Our experimental data indicate that glutathione might be involved in the non-oxidative metabolic pathways of halothane. Furthermore, (+)-catechin seems capable of protecting against the direct toxic effect of halothane metabolites resulting from the reductive pathways.
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PMID:Halothane hepatotoxicity in glutathione depleted rats. 362 65

The mechanisms of bromobenzene hepatotoxicity in vivo were studied in mice. The relationships among glutathione (GSH) depletion, lipid peroxidation, loss of protein thiols, disturbed calcium homeostasis and liver necrosis were investigated. Liver necrosis (as estimated by the serum glutamate-pyruvate transaminase (SGPT) level) appeared between 9 and 12 hr and increased at 18 hr. Lipid peroxidation which was already detectable at 6 hr in some animals, increased thereafter showing a good correlation with the severity of liver necrosis. Despite a quite fast depletion of hepatic GSH, a significant decrease in protein thiols could be observed at 12-18 hr only. Loss of protein thiols in both whole liver and subcellular fractions (microsomes and mitochondria) was correlated with lipid peroxidation. Also a good inverse correlation was seen between lipid peroxidation and the calcium sequestration activity of liver microsomes and mitochondria. The treatment of mice with desferrioxamine (DFO) after bromobenzene-intoxication completely prevented lipid peroxidation, loss of protein thiols and liver necrosis in the animals sacrificed 15 hr after poisoning. When, however, the animals were examined at 24 hr, although the general correlation between lipid peroxidation and liver necrosis was held, in some animals (about 30% of the survivors) elevation of SGPT was observed in the virtual absence of lipid peroxidation. It seems likely therefore that the liver damage seen during the first phase of bromobenzene-intoxication is strictly related to lipid peroxidation. It is, however, possible that in some animals in which for some reason lipid peroxidation does not develop, another mechanism of liver necrosis unrelated to lipid peroxidation occurs at later times.
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PMID:Lipid peroxidation, protein thiols and calcium homeostasis in bromobenzene-induced liver damage. 367 24

Previous data have demonstrated that methyl chloride (MeCl) is toxic to B6C3F1 mice under both acute and chronic exposure conditions, and that conjugation of MeCl with glutathione (GSH) is a key step in the metabolism of MeCl. This study examined the role of GSH in mediating the acute toxicity of MeCl to liver, kidney, and brain of male B6C3F1 mice. The lethal effects of a single 6-hr inhalation exposure of B6C3F1 males to 2500 ppm MeCl were completely prevented by pretreatment with the GSH synthesis inhibitor, L-buthionine-S,R-sulfoximine (4 mmol L-BSO/kg, ip 1.5 hr prior to MeCl exposure). GSH levels (measured as nonprotein sulfhydryl) in liver and kidney were depleted to 19 and 25% of control values, respectively, at the start of the exposure; the ratio of dead/exposed mice during the 18-hr postexposure declined from 14/15 mice to 0/10. Also, the LC50 for MeCl increased from 2200 to 3200 ppm in male mice pretreated with BSO. The hepatic toxicity of MeCl was detected by increased alanine aminotransferase (ALT) activities in serum 18 hr after a 6-hr exposure to 1500 ppm MeCl (2147 +/- 1327 IU/liter vs 46 +/- 6 in controls). Liver toxicity was inhibited when B6C3F1 males were depleted of GSH prior to MeCl exposure by BSO pretreatment (43 +/- 2), fasting (100 +/- 47), or injection of diethyl maleate (42 +/- 16). The effects of GSH depletion on MeCl toxicity to brain and kidney were determined in B6C3F1 males exposed to 1500 ppm MeCl 6 hr/day, 5 days/week for 2 weeks, with and without daily pretreatment with 2 mmol L-BSO/kg. This dose of BSO depleted hepatic and renal GSH by 28 and 60%, respectively, at the start of MeCl exposure. BSO-pretreated mice were protected from the central nervous system toxicity of MeCl, as assessed by microscopic examination of the granule cell layer of the cerebellum. BSO pretreatment also inhibited the renal toxicity of MeCl as measured by incorporation of [3H]thymidine ([3H]TdR) into renal DNA, an indicator of cell regeneration after cortical necrosis. [3H]TdR incorporation was 105 +/- 10,337 +/- 40, and 60 +/- 15 dpm/microgram DNA in nonexposed controls, MeCl, and MeCl + BSO treatment groups, respectively. These results indicate that GSH is an important component in the toxicity of MeCl to multiple organ systems in B6C3F1 mice. Reaction of MeCl with GSH appears to constitute a mechanism of toxication, contrary to the role usually proposed for GSH in detoxifying xenobiotics.
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PMID:Inhibition of the acute toxicity of methyl chloride in male B6C3F1 mice by glutathione depletion. 376 38

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


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