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)

Hepatotoxicity of diethyldithiocarbamate (DDC) was investigated in rats. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were markedly elevated 24 hr after subcutaneous administration of DDC and histologically, the liver showed submassive necrosis. A sustained inhibition in the liver of Cu,Zn-superoxide dismutase (Cu-SOD) activity was observed following DDC treatment. DDC produced a significant loss in liver reduced glutathione (GSH) level after 1 hr, but the nadir was observed later than that of Cu-SOD. Catalase activity decreased gradually from 7 hr. Thiobarbituric acid reactive substances (TBARS) in the liver were significantly increased from 15 hr. Hepatic haemodynamics were scarcely changed up to 15 hr. Desferrioxamine (a chelator of iron) and piperonyl butoxide (an inhibitor of cytochrome P-450) prevented DDC-induced increases of both ALT and TBARS, but GSH did not, DDC hepatotoxicity was not changed by phenobarbital induction. Thus, we have shown that subcutaneous dose of DDC caused hepatotoxicity in rats. Although the exact sequence of its hepatotoxic factors is unproven, it seems likely that lipid peroxidation through the dysfunction of antioxidant defence factors and a toxic metabolite contribute to the formation of this liver injury.
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PMID:Hepatotoxicity of diethyldithiocarbamate in rats. 196 45

Male and female Sprague-Dawley rats were administered the sodium salt of monochloroacetic acid (SMCA) by oral gavage for a period of 90 consecutive days. Dosage levels of 15, 30, 60 or 120 mg/kg per day were employed. SMCA clearly induced toxicity in both females and males, with the greatest severity in the male animals. Both the liver and kidneys were identified as target organs. At 120 mg/kg per day, 30% of females and 80% of the males died, most within the first 2 days of treatment. Hemorrhagic and congested lungs (possibly a postmortem change) were seen in the early deaths (1-3 days) whereas liver lesions were observed in later deaths. In addition, there was nephrotoxicity as evidenced by elevated creatinine, blood calcium (BCAL), and blood urea nitrogen (BUN) levels. Hepatotoxicity was indicated by increases in the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Both organs showed increased organ-to-body weight ratios. Microscopic examination revealed a significant (P less than or equal to 0.001) increase in chronic renal nephropathy and increased splenic pigmentation at 60 mg/kg per day in the males. Based on the observation of toxicity at all treatment levels in males, a lowest observed adverse effect level (LOAEL) of 15 mg/kg per day is proposed for a 90-day exposure to SMCA by oral gavage to the Sprague--Dawley rat.
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PMID:Ninety-day toxicity study of sodium monochloroacetate in Sprague-Dawley rats. 203 Dec 51

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

Furazolidone (FZ) was administered to 42-day-old female Japanese quails as a feed additive at doses of 0, 200, 400, 600 and 800 ppm for a period of 28 days. Dose-dependent effects were observed. High levels of FZ (600 and 800 ppm) significantly altered growth, decreased feed consumption, caused marked atrophy of the ovaries and oviducts leading to cessation of egg laying, and resulted in higher mortality. Hepatotoxicity was evidenced by an increase in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase and a decrease in serum total protein, in addition to degenerative changes of the hepatocytes in FZ-treated birds. A rise in serum urea was also observed. Symptoms leading to death included a loss of appetite causing emaciation followed by nervous disturbances (compulsive movements and circling). No signs of cardiomyopathy were observed. Japanese quails did not tolerate FZ at a concentration (400 ppm) recommended for the prevention of salmonellosis in poultry.
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PMID:Toxicological and biological studies on Japanese quails fed graded levels of furazolidone. 209 13

The hepatotoxic and mutagenic potentials of 2-nitropropane, nitromethane, and nitroethane were compared. Hepatotoxicity was assessed biochemically and histopathologically in BALB/c mice. In male mice, plasma activities of the hepatic enzymes sorbitol dehydrogenase, alanine aminotransferase, and aspartate aminotransferase were significantly elevated 48, 72, and 96 hr after ip administration of 9 mmol/kg 2-nitropropane, but not at 24 hr and not after administration of smaller doses of 2-nitropropane nor after nitromethane or nitroethane (9 mmol/kg). In female mice a dose of 6.7 mmol/kg of 2-nitropropane was sufficient to cause hepatotoxicity. The histopathological evaluation supported the biochemical results, and livers of mice that had received 2-nitropropane (9 mmol/kg) showed damage, particularly in the periportal region. Mutagenicity was tested in Salmonella typhimurium tester strains TA98, TA100, and TA102. Both 2-nitropropane and its anionic form, propane-2-nitronate, were mutagenic but the nitronate was the more powerful mutagen. Nitromethane, nitroethane, nor their nitronates caused an increase in the number of revertant colonies over those seen in control plates. The results suggest that the primary nitroalkanes are much less hepatotoxic and mutagenic than 2-nitropropane.
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PMID:Comparison of the hepatotoxicity in mice and the mutagenicity of three nitroalkanes. 267 74

Polychlorinated dibenzofurans are ubiquitous environmental pollutants which have great potential for human exposure. To characterize the toxicity of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF), male F344 rats were administered a single oral dose of 0, 100, 250, 500, 1000, or 2000 micrograms 4PeCDF/kg. A progressive and dose-dependent loss of body weight was evident by 3 days after treatment. Signs of toxicity included piloerection, hair loss, hypoactivity, morbidity, and death. Death occurred as soon as 14 days after treatment and continued throughout the 35-day observation period. The LD50/35 was estimated to be 916 micrograms/kg with a 95% confidence interval of 565-1484 micrograms/kg. Dose-dependent increases were observed in serum cholesterol, triglyceride, and bile acid concentrations and in sorbitol dehydrogenase and aspartate aminotransferase activities. The hematocrit, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentrations were depressed in a dose-dependent fashion. Hepatic ethoxyresorufin-O-deethylase (EROD) activity was increased in all treatment groups approximately 25 times above that of control animals. Lymphoid depletion in the thymus and spleen was observed in the three highest doses and thymic atrophy was present at all dose levels. Absolute liver weight and the liver:body weight ratio were significantly increased above controls. Hepatotoxicity was dose-dependent and was characterized by lipid accumulation resulting in hepatocytomegaly. Epithelial hyperplasia and focal ulcerations of the forestomach was observed in animals administered 500 micrograms 4PeCDF/kg. Spontaneous cardiomyopathy was exacerbated by treatment with 2000 micrograms/kg. Since 4PeCDF and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produce a similar spectrum of toxic effects, the biochemical mechanism(s) of toxicity for these chemicals may be similar.
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PMID:The acute toxicity of 2,3,4,7,8-pentachlorodibenzofuran (4PeCDF) in the male Fischer rat. 322 Feb 3

Prior consumption of a diet containing the food antioxidant, butylated hydroxyanisole (BHA), by female mice prevented the development of or minimized the acute liver damage caused by monocrotaline, acetaminophen, or bromobenzene. In contrast, neither the incidence nor the severity of carbon tetrachloride-induced hepatotoxicity was affected by dietary BHA. Hepatotoxicity was judged by plasma alanine aminotransferase and aspartate aminotransferase levels, hepatic cytochrome P-450 content, and liver histology. The protective effect of BHA against acetaminophen-induced hepatotoxicity was not demonstrated in male mice. The observed protection by dietary BHA against acetaminophen- and bromobenzene-induced hepatotoxicity was associated with the increase of liver glutathione. It is concluded that the protective action of BHA is dependent upon the nature of the toxic agent.
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PMID:Protective role of dietary butylated hydroxyanisole against chemical-induced acute liver damage in mice. 685 90

Increases in the use of methanol (MeOH) as a transportation fuel would result in greater potential for inhalation exposure. Because oral exposure to MeOH potentiates the hepatotoxicity of carbon tetrachloride (CCl4), we examined the ability of inhaled MeOH to potentiate CCl4 hepatotoxicity and the time course of injury and recovery. Adult male F-344 rats were exposed to 0 or to 10,000 ppm MeOH by inhalation for 6 h and gavaged with 0.075 ml CCl4/kg 24 h later. Hepatotoxicity was assessed 0.5, 1, 1.5, 2, 3, 7, 15, 30, and 61 d after CCl4 exposure. For CCl4 alone, hepatotoxicity was most severe at 0.5 and 1 d, when minimal centrilobular hepatocellular necrosis and predominately mild centrilobular hepatocellular vacuolar degeneration occurred. By d 3, the livers from the CCl4 rats were histologically normal. For MeOH+CCl4, peak severity of hepatic injury was at 1 and 1.5 d, when moderate centrilobular necrosis and moderate/marked centrilobular degeneration occurred. MeOH+CCl4 resulted in serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that were increased, relative to CCl4 alone, 171- and 113-fold, respectively, on d 1, and 166- and 140-fold, respectively, on d 1.5. Significant serum elevations in MeOH+CCl4 rats, relative to CCl4 alone rats, were present until d 7 and d 15 for AST and ALT, respectively. By d 3 and d 7, degeneration and necrosis, respectively, due to MeOH+CCl4 were essentially resolved. On d 7, the MeOH+CCl4 hepatic injury consisted mainly of chronic inflammation and centrilobular fibrosis. By d 30, the livers of MeOH+CCl4 rats were histologically normal. These data demonstrate that inhaled MeOH potentiates the hepatotoxicity of orally ingested CCl4, increasing the severity of CCl4 hepatotoxicity as well as the time required for recovery.
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PMID:Potentiation of carbon tetrachloride hepatotoxicity by inhaled methanol: time course of injury and recovery. 756 18

The present research was conducted to evaluate the effect of mitogen pre-exposure on CCl4-induced hepatotoxicity. Male Wistar rats were administered a single i.p. injection of CCl4 (0.3 ml kg-1 in corn oil) 48 h following either a single dose of lead nitrate (0.33 mg kg-1) or distilled water via i.v. injection. Hepatotoxicity, as measured by serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, was monitored 6, 24, 48, 72 and 120 h after CCl4 exposure. The lead nitrate-pretreated rats displayed markedly lower serum ALT and AST levels at 24, 48 and 72 h than rats pretreated with distilled water. However, treatment with the antimitotic agent colchicine did not alter the lead-induced protection. These findings suggest that the lead-induced protection is not associated with the major mitogenic response of lead, despite its strong temporal association. A critical review of the available toxicological data also argues against the lead protection being a function of its capacity to inhibit cytochrome P-450.
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PMID:Decrease in hepatotoxicity by lead exposure is not explained by its mitogenic response. 778 58

We determined whether the paracrine liver endothelin (ET) system participates in the pathogenesis of CCl4-induced hepatotoxicity. Wistar-Kyoto rats were divided into four groups: a bosentan-treated group with CCl4 intoxication, a vehicle-treated group with CCl4 intoxication, a nontreated control group, and a bosentan-treated control group. Hepatotoxicity was assessed by determination of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Tissue ET-1 concentrations and expression of endothelin receptor subtypes were analyzed. The liver tissue levels of ET-1 in rats with CCl4 intoxication were significantly higher than in normal rats. Scatchard analysis revealed no differences in the density and binding constants of ETA and ETB receptors between rats with CCl4 intoxication and controls. Bosentan treatment of rats undergoing CCl4 inhalation resulted in significant protection against elevation of ALT, AST, LDH, and bilirubin. In conclusion, this study showed that the paracrine ET system in involved in the pathogenesis of CCl4-induced hepatotoxicity and that blockade of the stimulated liver endothelin system reduces CCl4-induced liver injury.
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PMID:Protective effects of the mixed endothelin receptor antagonist bosentan in rats with CCL4-induced liver injury. 858 41


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