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)

To exclude the possibility that changes in hepatotoxicity and biotransformation were induced by diabetogen administration, the influence of long-lasting experimental insulin-dependent diabetes on the activities of benzphetamine demethylase, styrene oxide hydrolase, and UDP-glucuronosyl-transferases toward 1-naphthol, diethylstilbestrol, estrone and testosterone, and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and sulfobromophthalein was studied. Adult male Sprague-Dawley rats injected with 45 mg streptozotocin/kg rapidly developed the classical symptoms of diabetes which persisted throughout the 90-day test period. Ketonemia was detectable at 6 but not at either 35 or 90 days after streptozotocin administration. After acute challenge with bromobenzene or carbon tetrachloride (CCl4), aspartate and alanine aminotransferase activities in rats diabetic for 35 and 90 days were markedly higher than those in normal rats, suggesting that diabetes potentiated the hepatotoxicity of these chemicals. Administration of 25 microliters CCl4/kg, ip, to diabetic rats decreased enzyme activities toward benzphetamine, sulfobromophthalein, 1-chloro-2,4-dinitrobenzene, and 1-naphthol. In normal rats, a dose of 400 microliters CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 microliters/kg, ip) elicited opposing responses in diabetic and normal rats in N-demethylase activity, in UDP-glucuronosyltransferase activity toward 1-naphthol, estrone, and testosterone, and in glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Total cytochrome P450 concentrations were reduced by both induction of diabetes and hepatotoxicant challenge. Thus, chronic uncontrolled diabetes alters the response of hepatic xenobiotic biotransformation enzymes in a non-uniform, substrate-dependent manner, independent of initial diabetogen effects. The role of cytochrome P450j in potentiating CCl4 toxicity is discussed.
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PMID:The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats. 335 67

This study was undertaken to compare the sensitivity of the thyrotrophs to that of other tissues to T4 treatment in hypothyroid patients. To do so, we measured serum total and free thyroid hormones and TSH, in addition to several serum markers of peripheral tissue response to thyroid status, in 21 hypothyroid patients treated with 50-micrograms increments of T4 to a maximum of 200 micrograms daily (group I) and in 104 clinically euthyroid patients receiving a long term constant replacement dose (group II). In group I patients, dose-dependent increases (P less than 0.05) in serum glutathione S-transferase, sex hormone-binding globulin, and angiotensin-converting enzyme occurred, whereas serum T4-binding globulin, creatine kinase, and creatinine levels decreased (P less than 0.05). In both patient groups, abnormally high levels of glutathione S-transferase, sex hormone-binding globulin, angiotensin-converting enzyme, alanine aminotransferase, and gamma-glutamyl transferase were found in some patients during treatment. One or more of these biochemical abnormalities suggestive of hyperthyroidism occurred in 15 (71%) group I patients and 27 (26%) group II patients. These were associated with an undetectable serum TSH (less than 0.1 microU/ml) and raised free T4 concentrations in 13, and raised free T3, T4, and T3 concentrations in only 8, 6, and 1 group I patients, respectively. In group II patients, they were more closely associated with an undetectable TSH (67%) or raised free T4 (85%) level than with raised concentrations of free T3 (33%), T4 (26%), or T3 (0%). The use of high sensitivity TSH assays will permit more accurate adjustment of T4 replacement and minimize abnormalities in peripheral tissue biochemistry indicative of overtreatment.
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PMID:Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement. 379 54

The measurement of plasma glutathione S-transferase (GST) concentrations have been used to assess the changes in hepatocellular integrity which occur following general anaesthesia. Of 20 selected patients, who received halothane for minor urological procedures, 16 showed a small transient rise in GST between 1 h and 3 h after anaesthesia. Similar changes were also observed in 8 consecutive patients who received halothane for various operative procedures. In 3 of these 28 patients a marked secondary rise in plasma GST was observed 24 h after anaesthesia. No significant changes in ALT were observed in either of the groups of patients. These data indicate two possible phases of hepatotoxicity following halothane administration which results in a transient impairment in hepatocellular integrity in the majority of patients who undergo anaesthesia with this agent.
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PMID:Impaired hepatocellular integrity during general anaesthesia, as assessed by measurement of plasma glutathione S-transferase. 381 53

A specific radioimmunoassay (RIA) has been developed that has sufficient sensitivity to allow measurement of the changes in plasma and tissue glutathione S-transferase (GST) YaYa concentrations which occur following thyroid hormone administration in the rat. Using the RIA it was demonstrated that the only tissues that had significant amounts of GST YaYa were liver, small gut and kidney. Administration of triiodothyronine (T3) or thyroxine (T4) resulted in increases in plasma GST YaYa concentration and in animals given high doses of T4 plasma alanine aminotransferase activity was also elevated. Thyroid hormone administration produced a significant fall in the hepatic content of GST YaYa and in total GST activity, as assessed using 1-chloro-2,4-dinitrobenzene as substrate. It is concluded that the elevated plasma GST YaYa concentrations observed following administration of thyroid hormones result from hepatic damage, not from induction of hepatic synthesis of the enzyme.
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PMID:Hepatic damage in the rat following administration of thyroxine or triiodothyronine, assessed by measurement of plasma glutathione S-transferase YaYa concentrations. 381 55

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

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

Plasma glutathione S-transferase (GST) basic and N/A2b concentrations have been measured by specific radioimmunoassay in serial samples taken from patients admitted following a paracetamol overdose. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also measured. The sensitivities of the various measurements for detecting hepatocellular damage were compared. The measurement of either basic or N/A2b GST proved equally sensitive for detecting liver damage and both were superior to aminotransferase measurements. The abnormalities in GST were, on average, approximately 5- to 10-fold greater than the conventional aminotransferase measurements provided that correct timing of sampling was employed. The data presented suggest GST measurement is a sensitive non-invasive method for investigating acute drug-induced hepatotoxicity. The short plasma half-life of GST also allows early recognition of when active cellular damage has ceased.
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PMID:Plasma glutathione S-transferase measurements by radioimmunoassay: a sensitive index of hepatocellular damage in man. 398 35

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

Assay conditions of human liver glutathione S-transferase and its activity in human serum from liver disease patients were investigated. One mmol/l reduced glutathione, and 1 mmol/l-1-chloro-2,4-dinitrobenzene, pH 6.5, were used for the measurement, because of the very low non-enzymatic conjugation. Glutathione S-transferase activity was inhibited by bilirubin, but this inhibition was counteracted by the presence of a low concentration of albumin. The normal human serum glutathione S-transferase activity was 5.2 +/- 2.4 I.U./l (mean +/- S.D.), and was not influenced by any differences of age, sex or leukocyte count. A significant increase in serum enzyme activity was noted in cases of acute hepatitis with GPT exceeding 200 I.U./l, primary hepatoma and metastatic liver cancer. Some of the cases with fulminant hepatitis showed extremely high values. The degree of correlation between serum glutathione S-transferase and GOT or GPT was high in acute hepatitis, with GOT or GPT exceeding 200 I.U./l, in fulminant hepatitis, primary hepatoma and gall stones, while in chronic hepatitis and liver cirrhosis it was low. In cases of acute hepatitis and fulminant hepatitis, the disappearance of serum glutathione S-transferase from the blood was much faster than that of GOT and GPT. Serum glutathione S-transferase measurements will provide new and unique information for the diagnosis of acute liver diseases.
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PMID:Serum glutathione S-transferase activity in liver diseases. 625 85

The relations between serum transaminase activity and the hepatic contents of glutathione and lipid peroxide were examined following oral administration to rats of butylated hydroxytoluene (BHT; 500 or 1000 mg/kg). The glutathione level rapidly diminished and reached a minimum at 6 hr after BHT administration. The period of depletion was dependent on dose: restoration of the glutathione level took longer in high-dose rats than in low-dose rats. The content of hepatic lipid peroxide was not markedly changed by BHT throughout the experimental period. The activity of glutathione S-transferase was not affected until 12 hr after BHT administration but, thereafter, it increased with time and was accompanied by elevation of the glutathione level. Though the activities of serum glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase were not affected by low-dose BHT, they increased rapidly in the high-dose rates after a lag period of about 6 hr and reached a maximum at 24 hr after administration; at that time, the livers of the high-dose rats showed centrilobular necrosis. The results indicate that acute hepatic injury was induced by the high-dose BHT. Pretreatment with cobaltous chloride inhibited the increase in the activities of the serum transaminases produced by the high-dose of BHT accompanying the depletion of microsomal cytochrome P-450 content and the induction of glutathione content. These observations suggest that hepatic damage was associated with prolonged depletion of glutathione rather than with lipid peroxidation in the liver, and that the activated metabolites of BHT rather than the parent compound induced the tissue damage.
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PMID:On the mechanism of butylated hydroxytoluene-induced hepatic toxicity in rats. 646 78


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