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)

Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.
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PMID:Mechanistic studies of the inhibition of hepatic uroporphyrinogen decarboxylase in C57BL/10 mice by iron-hexachlorobenzene synergism. 380 Sep 66

Two oral doses of 1,2-dibromoethane (10-300 mumol/kg) were given to adult female rats 21 and 4 hours before sacrifice. Then hepatic DNA damage, ornithine decarboxylase, cytochrome P-450 content, glutathione content and serum alanine aminotransferase activity assays were performed. In addition, DNA damage was assessed in blood, bone marrow, kidney, spleen and thymus. Of the six organs studied, liver showed the largest amount of DNA damage. Doses at or above 10 mumol/kg EDB caused DNA damage as determined by the alkaline elution technique. Far greater doses (300 mumol/kg, 56.4 mg/kg) of EDB were required to cause other biochemical effects, such as increased activity of ornithine decarboxylase. Thus, the carcinogen EDB caused substantial DNA damage at doses far below those required to show other biochemical effects or frank liver toxicity. DNA damage occurred at a dose level 40-fold lower than that demonstrated in previous studies.
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PMID:1,2-Dibromoethane causes rat hepatic DNA damage at low doses. 380 Oct 22

Compound LY171883 caused dose-related and reversible hepatomegaly in male Fischer 344 rats. Histological examination revealed hepatocellular hypertrophy with no other evidence of liver disease. There were only minor changes in serum glucose, total bilirubin, alkaline phosphatase, and alanine transaminase which were generally unrelated to dose and dissociable from the hepatomegaly. Total liver DNA increased but the DNA concentration decreased, indicating that liver growth involved a combination of hypertrophy and hyperplasia. Total liver protein and RNA increased. Hepatic mitochondrial protein content increased but cytochrome oxidase activity was not changed. There were minor changes in mitochondrial respiratory parameters; however, all the values were in the normal range and there was no indication of mitochondrial toxicity. Microsomal protein, drug-metabolizing activity, and cytochrome P-450 increased, but glucose-6-phosphatase activity was not changed. The induction of drug-metabolizing enzymes and absence of toxicity were evidence that the hepatomegaly was an adaptation to an increased functional load in the liver. An increase in catalase activity suggested that the response may have also involved peroxisomes. In addition to rats, LY171883 administration caused hepatomegaly in mice and hamsters at daily exposures exceeding 100 mg/kg. The response was not observed in guinea pigs, beagle dogs, or rhesus monkeys given maximum tolerated doses, indicating LY171883-induced hepatomegaly is not a response common to all species. The doses required to elicit hepatomegaly greatly exceeded doses that produce pharmacological efficacy in animals and those that are expected to be used clinically. Since humans will not receive doses comparable to those given rodents, and considering that the primate species tested did not experience hepatomegaly, it is unlikely that the effect observed in rodents can be extrapolated to humans.
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PMID:Characterization of liver enlargement induced by compound LY171883 in rats. 384 Jan 8

Murine IFN(gamma) and human IFN(alpha)-AD:Bgl were compared over a limited dose range and after single and multiple dosing for their effect on male mouse liver oxidative and conjugative drug metabolizing enzymes. Both IFNs depressed the microsomal cytochrome P-450 concentration but did not alter cytosolic glutathione S-transferase nor microsomal UDP-glucuronosyltransferase activity. Both IFNs showed some slight hepatotoxicity (elevated serum ALT), alpha AD:Bgl more than gamma, especially after multiple dosing. While the IFNs did not produce significant increases in liver weight, they did increase the yield of microsomal protein. The increased endoplasmic reticulum may compensate for the decreased cytochrome P-450 concentration and so account for the lack of observed effect of the IFNs on hexobarbital sleep times in vivo. Overall, the minimal effects of murine gamma-IFN on the mouse liver were no different than those of human alpha AD:Bgl.
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PMID:Effect of murine gamma-interferon on the mouse liver and its drug-metabolizing enzymes: comparison with human hybrid alpha-interferon. 392 33

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

Previous observations that valproic acid (VPA) causes hepatic damage prompted us to investigate the effect of large doses of the drug (0.6, 1.2 and 1.8 mmol/kg/day) on a number of liver enzymes located on different subcellular fractions. In mitochondria, glutamate dehydrogenase, aspartate aminotransferase and ornithine carbamoyltransferase were significantly increased (1.8 mmol/kg/day). In microsomes, gamma-glutamyltransferase activity increased significantly (1.8 mmol/kg) and cytochrome P-450 content decreased significantly (1.2 and 1.8 mmol/kg). In cytosol, both aspartate and alanine aminotransferase activities were increased at all dose levels. These results indicate that VPA induces dose-dependent changes in some liver enzyme activities.
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PMID:Effect of sodium valproate on subcellular fraction enzymes in rat liver. 393 26

Male Fischer 344 rats were exposed to halothane, enflurane or isoflurane vapour 20 p.p.m., or air, for up to 30 weeks. None of the anaesthetic agents led to hepatocellular necrosis. Exposure to halothane resulted in slight increases in serum alanine aminotransferase activity, an increase in the size of the liver, an increase in hepatic microsomal cytochrome P-450 content and a minimal amount of fatty change in the liver. None of these effects were observed during exposure to enflurane or isoflurane. Urinary fluoride excretion was increased during exposure to either enflurane or isoflurane. Using this increase as an index of anaesthetic biotransformation, we found that the extent of biotransformation of isoflurane was only slightly lower than that of enflurane.
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PMID:Effects of chronic inhalation of halothane, enflurane or isoflurane in rats. 396 17

Groups of male Sprague-Dawley rats received po doses of cyclopiazonic acid (CPA) on four consecutive days at 0.0, 0.2, 2.0, 4.0, or 8.0 mg kg-1 days-1. Clinical signs of toxicity were observed only in the two highest dose groups. Rats in the highest dose group exhibited abnormal behavior, diarrhea, and other signs of toxicity after several days of dosing, and most were moribund before the last scheduled dose was administered. Liver and spleen were more severely affected than other organs in the two highest dose groups. Livers contained diffuse pycnotic nuclei and, in some high-dose rats, focal areas of coagulative necrosis. In the high-dose group aspartate and alanine aminotransferase activities were elevated, cytochrome P-450 concentration was decreased, and glutathione S-transferase activity was unchanged. Spleens were hemorrhagic and white pulp contained necrotic lymphocytes. White cell counts were decreased in a dose-related manner in the two highest dose groups. The gastrointestinal tract of high-dose rats contained pycnotic nuclei, and sites of necrosis were observed in stomach, but these lesions were limited to several animals, and were generally mild. Pathologic changes in conjunction with decreased feed and water intake probably contributed to the general deterioration of high-dose rats that resulted in death.
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PMID:Toxicity of the mycotoxin, cyclopiazonic acid, to Sprague-Dawley rats. 396 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

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


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