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)

Hypocalcemic vitamin D-depleted rats received either 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] or calcium p.o. in order to study the effects of plasma calcium normalization, resulting from hormone or dietary calcium administration, on the hepatic response to bromobenzene (BB). Results showed that 1,25(OH)2D3 administration induced a rise in the circulating aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase after BB administration significantly greater than in unsupplemented rats. The volumic density of necrosis was not, however, increased by 1,25(OH)2D3 whereas the proportion of acidophilic cells surrounding the necrotic area and the ratio of acidophilic to necrotic cells were significantly increased suggesting the presence of regenerating parenchyma. Oral calcium yielded an increase comparable to that of 1,25(OH)2D3 in apparent BB toxicity which was accompanied by a significant rise in both the volumic density of necrosis and of acidophilic cells but the ratio of acidophilic to necrotic cells was not increased by dietary calcium. The amount of cytochrome P-450 lost after BB administration, the covalent binding of BB metabolites to cellular proteins in vitro and the total liver glutathione content were not changed by either 1,25(OH)2D3 or calcium supplementation. Results show that hypocalcemic vitamin D-depleted rats are protected partially against BB toxicity; this protection does not seem to be due to a decrease in the hepatic metabolism of BB but seems to be related to the hypocalcemic state; on the other hand, the active regenerating process which seemed more apparent in 1,25(OH)2D3-treated than in all other animals may have contributed to offset partly the cellular damage induced by the toxin in the hormone-treated group.
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PMID:Influence of the vitamin D hormonal status on the hepatic response to bromobenzene. 361 37

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

Protective effect of malotilate on the liver injuries induced by several hepatotoxins was studied in mice and rats. Malotilate suppressed the elevation of plasma glutamate pyruvate transaminase (p-GPT) activity induced by chloroform (CHCl3) in rats when the animals were treated with 25 mg/kg or more dose of malotilate at 6 hours prior to the treatment with CHCl3. The effect was observed even in the rats treated with malotilate 24 or 48 hours prior to the treatment with CHCl3. Malotilate, when orally administered 6 hours prior to treatment with hepatotoxins such as CHCl3, allyl alcohol, bromobenzene, dimethylnitrosamine or thioacetamide, suppressed the elevation of p-GPT activity, liver triglyceride content and/or the decrease of bromosulphalein clearance induced by these hepatotoxins in mice. Anethole trithione, which was used as a possible protective agent against chemical-induced hepatotoxicity, tended to normalize changes in the parameters induced by the most of these hepatotoxins, but enhanced the elevation of p-GPT activity induced by CHCl3. In a case of CHCl3-induced liver injury, the protective effect of malotilate was histopathologically confirmed. Malotilate and anethole trithione reduced p-nitroanisole 0-demethylation activity in rat liver 6 hours after the administration but increased or tended to increase the activity 48 hours after the administration. Malotilate showed a protective effect on the liver injury induced by CHCl3 even when the activity of drug metabolizing enzymes in the liver was increased, although anethole trithione enhanced the CHCl3-induced liver injury regardless of the activity of drug metabolizing enzymes.
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PMID:[Protective effect of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) on chemical-induced hepatotoxicity]. 379

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

Vitamin D-depleted and vitamin D-replete rats were treated with allyl alcohol (AA) or bromobenzene (BB). The severity of the hepatotoxicity was evaluated by the serum concentrations of aspartate aminotransferase, alanine aminotransferase and sorbitol dehydrogenase, the histomorphological appearance of the lesions, and the amount of cytochrome P-450 destroyed. The activity of the monooxygenases was also evaluated. All parameters indicated that vitamin D depletion alone did not lead to any signs of liver toxicity nor did it modify the pattern of toxicity of either AA or BB. However, the intensity of the response in the periportal (AA treatment) and in the centrilobular (BB treatment) zones was modified by the depletion. Vitamin D depletion was accompanied by increased hepatic damage due to AA while BB resulted in less hepatic damage in vitamin D-depleted compared to vitamin D-replete animals. The metabolic profile of the liver mixed function oxidases indicated that its intraacinar distribution was modified by the depletion. Although the overall activity toward the substrates studied was not changed by vitamin D depletion, two out of the three enzyme activities studied suggested that vitamin D-depleted rats were poorer "centrilobular metabolizers" and better "periportal metabolizers" than vitamin D-replete rats. These observations correspond to increased periportal and decreased centrilobular toxicity in vitamin D-depleted animals. These results suggest that vitamin D depletion associated with severe hypocalcemia may be associated with an intraacinar modulation of enzyme systems as well as with an intraacinar difference in the susceptibility of the liver to certain chemicals.
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PMID:Comparative hepatic response to bromobenzene and allyl alcohol in the vitamin D-replete and vitamin D-depleted rat. 399 32

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

The effects of bromobenzene, carbon tetrachloride, and N-nitrosodimethylamine (DMN) on hepatic glutathione S-transferase activity were studied in untreated and in phenobarbital- or ethanol-treated rats. In phenobarbital-treated rats, the isozymic composition of the hepatic cytosolic glutathione S-transferases was changed after giving hepatotoxic chemicals; glutathione S-transferases 2-2(AA), 3-3(A), 1-2(B), 3-4(C), and 4-4 + 5-5(D + E) were present in cytosol from control rats, but only glutathione S-transferases cochromatographing with transferases 4-4 + 5-5(D + E) were detected in rats given carbon tetrachloride or bromobenzene. A marked decrease in hepatic and an increase in serum glutathione S-transferase activity were also observed after carbon tetrachloride or bromobenzene treatment, but little change was seen after giving DMN. On the contrary, in untreated or ethanol-treated rats, DMN administration decreased hepatic glutathione S-transferase activity and caused an elevation in serum glutathione S-transferase activity. The isozymic composition of the hepatic cytosolic glutathione S-transferases after giving DMN to untreated rats was also altered, but the alteration was much less than that observed after giving carbon tetrachloride or bromobenzene to phenobarbital-treated rats. The elevation in serum glutathione S-transferase activity was accompanied by an increase in both serum glutamate-pyruvate transaminase activity and serum bilirubin concentrations. Thus, hepatic glutathione S-transferase activity was altered and released into serum after giving hepatotoxic chemicals, and the alteration in glutathione S-transferase activity was dependent on treatment with phenobarbital or ethanol.
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PMID:Alteration of hepatic glutathione S-transferases and release into serum after treatment with bromobenzene, carbon tetrachloride, or N-nitrosodimethylamine. 407 84

H2 receptor antagonist-hepatotoxicant interactions were evaluated in male Fischer-344 rats. The H2 receptor antagonists, cimetidine, ranitidine, oxmetidine, and 2-[2-(2-dimethyl-aminomethyl-5-furanylmethyl-thio)-ethylamino]-5-( 6-methyl- 3-picolyl)-4-pyrimidine trihydrohydrochloride (SK&F 93479) were administered (p.o.) at a dose of 0.143 mMoles/kg 30 minutes prior to hepatotoxicant treatment. Submaximal hepatotoxic doses (p.o.) of carbon tetrachloride (795 mg/kg), bromobenzene (748 mg/kg), chloroform (1,190 mg/kg), allyl alcohol (60 mg/kg), galactosamine (200 mg/kg, i.p.), and acetaminophen (1000 mg/kg) were employed. Hepatotoxicity was evaluated by determining serum alanine aminotransferase activity (ALT). Pretreatment with the H2 receptor antagonists did not significantly alter carbon tetrachloride or allyl alcohol hepatotoxicity. Bromobenzene and chloroform toxicities were unaffected by cimetidine, ranitidine, and oxmetidine pretreatment but were potentiated by SK&F 93479. Cimetidine and ranitidine decreased galactosamine mediated hepatotoxicity. Acetaminophen hepatotoxicity was markedly potentiated by ranitidine pretreatment but was unaltered by the other three H2 receptor antagonists. The mechanisms of hepatotoxicity potentiation or protection have not been determined, however, the lack of consistent H2 receptor antagonists effects indicates that it is unlikely that alterations in G.I. pH account for the effects observed. H2 receptor antagonist mediated changes in hepatotoxicant metabolism provide a more plausible mechanism of action, particularly in the cases of SK&F 93479 potentiation of bromobenzene and chloroform and ranitidine potentiation of acetaminophen hepatotoxicity.
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PMID:Effects of H2 receptor antagonists on the hepatotoxicity of various chemicals. 614 1

Diethyldithiocarbamate (DTC) and carbon disulfide (CS2), at nearly equimolar oral dose levels, protected mice against liver damage induced by carbon tetrachloride, chloroform, bromotrichloromethane, thioacetamide, bromobenzene, furosemide, acetaminophen, dimethylnitrosamine and trichloroethylene, as evidenced by the suppression of elevations in plasma GPT activity and liver calcium content, and of histopathological alterations. Both agents also prolonged hexobarbital sleeping time and zoxazolamine paralysis time in mice. DTC and SC, alone, given orally, decreased microsomal metabolism of several substrates (aniline, p-nitroanisole, hexobarbital, zoxazolamine, aminopyrine and 3,4-benzopyrene), CC14-induced lipid peroxidation, and cytochrome P-450 content. The loss of microsomal drug-metabolizing enzyme activity was also observed in the experiments in vitro using liver slices and isolated microsomes. Since a characteristic common to such diverse hepatotoxins is that they require metabolic activation before exhibiting hepatotoxicity, the protective mechanisms of DTC and CS2 may involve their interference with the process of metabolic activation of these hepatotoxins. The protective action of DTC may be mediated almost entirely through CS2 when administered orally and at least partly with parenteral administration, since, in CCl4-induced liver injury, DTC was most effective when given orally, while the action of CS2 was less dependent on the route of administration. Thus CS2 and CS2-producing agents in vivo such as dithiocarbamate derivatives and disulfiram may modify toxicological and pharmacological effects of foreign compounds by inhibiting microsomal drug-metabolizing enzyme activity in the liver.
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PMID:Protective effect of diethyldithiocarbamate and carbon disulfide against liver injury induced by various hepatotoxic agents. 629 43


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