Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The destruction of liver microsomal cytochromes P450 by a previously administered low dose of CCl4 has been widely accepted as the mechanism of CCl4 autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl4 (0.3 ml/kg, po) on the lethal effect of a subsequently administered high dose (5 ml/kg, po) was established in male Sprague Dawley rats. The protective dose permitted 100% survival, whereas only 15% survival was observed without it. Hepatotoxicity, measured by serum enzyme elevations (aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase) and histopathological changes 24 hr after the treatment with high dose, was similar in both the groups, even though the protective dose had significantly decreased liver microsomal cytochromes P450 (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl2 to decrease hepatic microsomal cytochrome P450 to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCl4. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCl4. Based on this observation, a premise that autoprotection results from augmented recovery from injury rather than decreased injury appears likely. Hence, the role of hepatocellular regeneration was evaluated by following 3H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl4, stimulated nuclear DNA synthesis measured by 3H-thymidine incorporation into nuclear DNA was increased and this remained high even after subsequent administration of high dose of CCl4. Forty-eight hr after the administration of a lethal dose of CCl4 alone (5 ml/kg, po), labelling index was slightly increased, but mitotic index was not increased. In the surviving rats (15%), both labelling index and mitotic index were significantly elevated after an additional 24 hr. In rats receiving the protective dose, a significantly greater elevation of labelling index as well as mitotic index occurred 48 hr after the administration of the same lethal dose of CCl4. These results suggest that hepatocellular regeneration stimulated by the protective dose, as a biological response recruited to overcome the accompanying limited injury, may augment and sustain tissue repair processes to permit tissue restoration even after the massive liver injury elicited by the subsequent large dose of CC14.
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PMID:Role of hepatocellular regeneration in CCl4 autoprotection. 204 7

The potentiation of CCl4 toxicity by pre-exposure to chlordecone (CD) is well established. Chlordecone-induced metabolism of CCl4 and suppressed hepatocellular repair have been offered as possible mechanisms for this potentiation. Recent work using the partially hepatectomized (PH) rat as a model for an actively regenerating liver has provided supportive evidence for the latter hypothesis. The present study was initiated to determine if metabolism and disposition of 14CC14 is altered in the PH rat, and if this is a contributing factor to the reported protective effect afforded by the PH procedure. Male Sprague-Dawley rats (150-175 g) maintained on dietary CD (10 ppm) for 15 days were partially hepatectomized or sham-operated (SH) on day 15. Another group of CD-pretreated rats received 0.9% CoCl2 (60 mg/kg, sc, qd for 2 days) in lieu of the surgical procedure. On day 16 the rats were challenged with a single dose of CCl4 (100 microL/kg, ip) containing 20 muCi 14CCl4. A radiolabel inventory consisting of exhaled 14CCl4, 14CO2 production, total hepatic 14C, free 14CCl4 and covalently bound 14C was taken over a 6-hr time period. Lipid peroxidation and serum enzyme activities [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] were measured in indices of toxicity. Neither CD pretreatment alone nor CoCl2 treatment alone produced significant alterations in metabolism of low dose (100 microliters/kg) CCl4. No significant difference in 14CCl4 recovery or 14CO2 production was detected for PH versus SH rats. Hepatic 14CCl4-derived 14C (per gram tissue) was greater in PH rats. Values for free 14CCl4, covalently bound 14C, and lipid peroxidation were similar for SH and PH rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Carbon tetrachloride metabolism in partially hepatectomized and sham-operated rats pre-exposed to chlordecone (Kepone). 248 48

Male New Zealand White rabbits were treated with microsomal enzyme inducers, inhibitors of hemoprotein synthesis or action, and glutathione precursor and depletor before they were orally given the median lethal dose (LD50) of aflatoxin B1 (AFB1; 0.4 mg/kg) at the start of a 7-day experimental period. The drugs administered, mean duration of illness (hours), and survival percentage were as follows: controls (saline solution)-85, 50%; phenobarbital (PB)-100, 100%; phenylbutazone-115, 67%; benzoflavone-39, 17%; stanozolol-67, 67%; cobaltous chloride (CoCl2)-46, 67%; piperonyl butoxide (PBO)-88, 100% cysteine (CYS)-68, 100%; ethyl maleate-71, 83%. Signs of toxicosis included decreased feed and water consumption, weight loss, dehydration, lethargy, and emaciation; some rabbits died or were euthanatized. Clinico-pathologic changes included increased serum aspartate aminotransferase (AST) activity by 24 hours and bilirubin concentration by 48 to 72 hours after AFB1 was given. Grossly, livers were pale or tan and friable, with prominent lobular architecture. Kidneys of affected rabbits were pale to dark red. Microscopically, livers were normal or had lesions as great as extensive necrosis, hemorrhage, mineralization, and bile duct proliferation. Treatment of rabbits with PB, CoCl2, PBO, and CYS protected against AFB1 hepatic pathology, and PB, PBO, and CYS also had protective effect against lethality. Ethyl maleate provided some protection against lethality and increased serum AST activity and bilirubin concentration. Toxicosis was enhanced by benzoflavone; phenylbutazone and stanozolol had litte influence.
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PMID:Effect of enzyme inducers and inhibitors and glutathione precursor and depleter on induced acute aflatoxicosis in rabbits. 680 67

The purpose of this investigation was to determine the utility of fast-twitch skeletal muscle troponin I (fsTnI) and urinary myoglobin (uMB) as biomarkers of skeletal muscle injury in 8-week-old Sprague-Dawley rats. fsTnI and uMB were quantified by enzyme-linked immunosorbent assay and compared with standard clinical assays including creatine kinase, aldolase, aspartate aminotransferase, and histopathological assessments. Detectable levels of uMB were normalized to urinary creatinine to control for differences in renal function. Seven compounds, including those with toxic effects on skeletal muscle, cardiac muscle, or liver, were evaluated. fsTnI was typically nondetectable (< 5.9 ng/ml serum) in vehicle-treated female and male rats but increased in a dose-dependent manner to at least 300 ng/ml in cerivastatin-induced severe fast-twitch specific myotoxicity. Minimal myopathy induced by investigational compounds BMS-600149 and BMS-687453 increased serum fsTnI to about 30-50 ng/ml, suggesting a reasonable dynamic range for detecting mild to severe skeletal muscle toxicity. In direct contrast, fsTnI was only marginally increased relative to population control values in rats treated with triamcinolone acetonide, which produces muscle atrophy or the cardiotoxins isoproterenol and CoCl2. uMB was typically nondetectable (< 1.6 ng/ml urine) in vehicle-treated female and male rats but increased to approximately 140, 300, and 30 ng/mg creatinine in rats treated with cerivastatin, BMS-687453, and triamcinolone acetonide, respectively. Cardiotoxicity also increased uMB in rats treated with isoproterenol and CoCl2 with urine concentrations ranging from 20 to 30 ng/mg creatinine. Severe hepatotoxicity (coumarin) did not significantly affect serum fsTnI or uMB levels. Collectively, these data suggest that fsTnI is specific for skeletal muscle toxicity, whereas uMB is nonspecific, increasing with skeletal muscle and cardiac toxicity. Accordingly, the complement of fsTnI and uMB, in conjunction with standard clinical assays may comprise a useful diagnostic panel for assessing drug-induced myopathy in rats.
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PMID:Biomarkers of drug-induced skeletal muscle injury in the rat: troponin I and myoglobin. 1962 85

Novel maleimide derivative 1-(4-Cl-benzyl)-3-Cl-4-(CF3-phenylamino)-1H-pyrrol-2.5-dione (MI-1) with cytostatic activity does not damage rat liver cells after intragastric administration. It is confirmed by alanine- and aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase activities in blood serum. Preliminary treatment with MI-1 partially prevents from liver cell damage caused by CoCl2. the content of thiobarbituric-active products, protein carbonyl groups, reduced glutathione and activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in the liver cell after one- and ten-days treatment with novel maleimide derivative have been studied. It has been determined that one-day administration of MI-1 has not caused significant changes of peroxidation process and antioxidant system in the liver cells. After ten days treatment the activity of glutathione-S-transferase has been increased, superoxide dismutase--two times decreased, but other parameters have not been significantly changed. Ten days injection of CoCl2 provokes some manifestations of oxidative stress in the liver cells that has been partially leveled by preliminary treatment with maleimide derivative.
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PMID:[Evaluation of hepatotoxicity of novel maleimide derivative with cytostatic activity and its effect on peroxidation process and antioxidant system in the liver]. 2038 51