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)

Administration of 500 mg/kg acetaminophen (APAP) to female B6C3F1 mice resulted in well-documented pathophysiological changes in the liver manifested as increased serum concentration of liver enzymes (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and serum sorbitol dehydrogenase), centrilobular congestion, and hepatocellular degeneration and necrosis. The role of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin 1 alpha (IL-1 alpha), on the hepatotoxicity of APAP was examined at 4, 8, 12, and 24 hr following APAP administration. Neutralization of TNF-alpha or IL-1 alpha with specific antibodies partially prevented the hepatotoxic effects of APAP at the 4- and 8-hr time points. In addition, prior administration of anti-TNF-alpha antibodies shortened the recovery time following APAP treatment. While IL-1 receptor antagonist (IL-1ra) had only a modest protective effect against APAP-induced liver damage, as determined by serum enzyme release, IL-1ra had no effect on the degree of hepatic congestion or necrosis at any of the time points examined. On the other hand, administration of antibodies against IL-1ra exacerbated APAP-induced liver toxicity. These results suggest that TNF-alpha and IL-1 alpha play an important role in the degree of damage and recovery that the liver undergoes following APAP intoxication.
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PMID:Histopathology of acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha. 899 8

The two conjugates, S-[N-(2-hydroxyethyl)carbamoylmethyl]glutathione (GSAAE), and its corresponding mercapturic derivative N-acetyl-S-[N-(2-hydroxyethyl)carbamoylmethyl]cysteine (NCySAAE) were administered to fasted Sprague-Dawley rats as putative metabolites of vinylidene chloride (VDC). Methylthioacetylaminoethanol (MAAE) was identified in the urine of GSAAE- or NCySAAE-treated rats (0.5-2.0 mmol/kg, i.p.), as well as in the urine of VDC-treated rats (0.5-2.0 mmol/kg, p.o.). The effects of VDC, GSAAE and NCySAAE on the kidney and liver were also examined using aspartate aminotransferase (ASAT). N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (beta 2-m) as urinary parameters of nephrotoxicity, and glutamate dehydrogenase (GLDH), sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALAT) as serum parameters of hepatotoxicity. Unlike treatment with VDC, treatment with both GSAAE and NCySAAE failed to cause kidney and liver toxicity. The results support the hypothesis that MAAE originates from the formation of GSAAE and further metabolization to NCySAAE, and that MAAE excretion does not reveal a pathway of reactive intermediates.
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PMID:Formation of GSH-derivatives as a pathway for inactive intermediates in vinylidene chloride-treated rats. 900 91

Healthy adult male desert sheep were experimentally infected with Fasciola gigantica, to investigate the influence of experimental fasciolasis on the pharmacokinetics of antipyrine and sulphadimidine. Each animal received 500 metacercariae orally. The experimental infection was confirmed histologically, by detection of Fasciola eggs in faeces and by measuring the activities of the enzymes sorbitol dehydrogenase (SD), glutamate dehydrogenase (GD) and aspartate aminotransferase (AST) in plasma during the course of the disease. Changes in the pharmacokinetics of antipyrine and sulphadimidine were reported in the experimentally infected animals. Significant prolongation of antipyrine half life was observed 16 weeks after infection. The half-life of sulphadimidine was also significantly prolonged 5, 9 and 16 weeks after infection. Clearance of the sulphonamide was decreased significantly 5 and 9 weeks after infection and it regained its pre-infection value 16 weeks after infection.
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PMID:The effect of experimental fascioliasis on the pharmacokinetics of antipyrine and sulphadimidine in desert sheep. 918 81

The association between hepatic lipidosis (HL) and disease in 59 anorectic, ketotic, lactating Holstein heifers and cows was investigated. Severe HL, as determined by histologic evaluation of liver tissue, was present in 46 animals; only half of these animals required intensive treatment for ketosis, and only half had serum biochemical evidence of liver disease, as determined by the presence of a last value of 2-fold or greater than the upper limit of the reference ranges for at least 2 of the 4 serum tests: gamma-glutamyl transferase, aspartate aminotransferase, and sorbitol dehydrogenase activities and bile acid concentrations. Most cattle with biochemical evidence of liver disease and severe HL had been lactating for 14 or more days. Cows that required intensive treatment inconsistently had serum biochemical evidence of liver disease. Although cattle with severe HL had significantly higher serum bilirubin concentrations and aspartate aminotransferase and sorbitol dehydrogenase activities than cattle with less severe lipidosis, the specificity of abnormally high serum sorbitol dehydrogenase activity or bilirubin concentration for severe lipidosis was only 8%. Abnormally high serum aspartate aminotransferase activity was 83% sensitive and 62% specific for severe lipidosis. Serum glucose and total carbon dioxide concentrations were significantly lower in cattle with severe lipidosis than in those with mild or moderate lipidosis, and low serum glucose or total carbon dioxide concentrations were rare in cattle without severe lipidosis. From these data, we conclude that the use of a single biochemical or histopathologic criterion to define severity of disease or degree of liver compromise in anorectic, ketotic cows results in the misidentification of many animals.
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PMID:Hepatic lipidosis in anorectic, lactating holstein cattle: a retrospective study of serum biochemical abnormalities. 929 78

Cisplatin [cis-dichlorodiammineplatinum (II)] is a widely used chemotherapeutic drug that is toxic to the kidney. Concurrent administration of cysteine together with vitamin E, Crocus sativus and Nigella sativa reduced the toxicity of cisplatin in rats. When administered i.p. for 5 alternate days with 3 mg/kg cisplatin, cysteine (20 mg/kg) together with vitamin E (2 mg/rat) an extract of Crocus sativus stigmas (50 mg/kg) and Nigella sativa seed (50 mg/kg) significantly reduced blood urea nitrogen (BUN) and serum creatinine levels as well as cisplatin-induced serum total lipids increases. In contrast, the protective agents given together with cisplatin led to an even greater decrease in blood glucose than that seen with cisplatin alone. The serum activities of alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase and alanine aminotransferase of cisplatin-treated rats were significantly decreased, whereas the activities of glutathione reductase and isocitrate dehydrogenase were significantly increased. Addition of cysteine and vitamin E, Crocus sativus and Nigella sativa in combination with cisplatin partially prevented many changes in the activities of serum enzymes. In cisplatin-treated rats, the liver activities of isocitrate dehydrogenase and aspartate aminotransferase were significantly increased, whereas much greater changes were found in the kidneys, with increased activity of glucose-6-phosphate dehydrogenase and decreased activities of alkaline phosphatase, isocitrate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase and gamma-glutamyl transferase, as well as a decreased phosphorylation to oxidation ratio in the mitochondria, indicating reduced adenosine triphosphate production. Also, administration of cysteine and vitamin E, Crocus sativus and Nigella sativa together with cisplatin partially reversed many of the kidney enzymes changes induced by cisplatin. Cysteine together with vitamin E, Crocus sativus and Nigella sativa tended to protect from cisplatin-induced falls in leucocyte counts, haemoglobin levels and mean osmotic fragility of erythrocytes and also prevented the increase in haematocrit. The results of this study indicate a basis for the toxic effects of cisplatin, and suggest a possible way of counteracting the toxicity by introducing protective agents such sulphydryl compounds, other antioxidants and extracts of natural products. It also appears that cells adapt to the effects of cisplatin through the induction of systems that produce NADPH, which in turn compensates the decrease of free sulphydryl groups. We conclude that cysteine and vitamin E, Crocus sativus and Nigella Sativa may be a promising compound for reducing cisplatin-toxic side effects including nephrotoxicity.
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PMID:Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cisplatin-induced toxicity in rats. 960 69

The purpose of this study was to relate dose-dependent hepatotoxicity stemming from prolonged exposure to sublethal concentrations of the cyclic heptapeptide microcystin-LR (Mcyst) to hepatic Mcyst concentrations and protein phosphatase activity. Mcyst is a potent inhibitor of protein phosphatase types 1 and 2A (PP1 and PP2A). Twenty male Sprague-Dawley rats were infused continuously with 0, 3, 6, or 9 micrograms Mcyst/day for 28 days using intraperitoneal mini-osmotic pumps containing highly purified toxin or saline. At the end of 28 days, dose-dependent increases in several serum biochemical tests including sorbitol dehydrogenase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and bile acids had occurred. Serum albumin decreased in a dose-dependent fashion. Liver activity of both PP1 and PP2A decreased in a dose-dependent manner, but with a relatively greater effect on PP2A than PP1. Liver cytosol Mcyst concentrations, measured by direct competitive ELISA, also increased in a dose-dependent manner, although at a higher rate than would be predicted from the incremental increase in dose given. This disproportional increase is suggestive of the bioaccumulation of Mcyst with increasing dose. Histopathological abnormalities included hepatocellular apoptosis and cytosolic vacuolation of principally zone 3 hepatocytes. Immunohistochemical stains revealed Mcyst predominantly within pericanalicular regions of zone 3 hepatocytes. It was concluded that prolonged exposure to sublethal concentrations of Mcyst results in multiple dose-dependent hepatotoxic effects that correspond to decreased hepatic serine/threonine protein phosphatase activity and increasing cytosolic Mcyst concentrations. The disproportional increase of hepatic Mcyst concentrations observed may suggest the bioaccumulation of toxin and an increasing relative risk of hepatotoxicity with increasing dose.
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PMID:Prolonged sublethal exposure to the protein phosphatase inhibitor microcystin-LR results in multiple dose-dependent hepatotoxic effects. 972 Jan 45

Effects of a single dose of betaine on the chloroform-induced hepatotoxicity were examined in adult male ICR mice. Administration of betaine (1000 mg/kg, ip) 1 to 7 hr prior to a chloroform challenge (0.25 ml/kg, ip) resulted in remarkable enhancement of hepatotoxicity as indicated by increases in serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. The potentiation of hepatotoxicity was most significant when mice were treated with betaine 4 hr earlier than chloroform. However, a 24 hr prior administration of betaine protected the animals from induction of the chloroform hepatotoxicity. Thus, its effect appeared to be highly dependent on the time lapse from the betaine pretreatment to the challenge of mice with chloroform. Betaine treated either 4 or 24 hr prior to sacrifice did not alter the hepatic contents of cytochrome P-450, cytochrome b5, or NADPH cytochrome P-450 reductase activity. Accordingly the hepatic microsomal p-nitroanisole O-demethylase, aminopyrine N-demethylase, or p-nitrophenol hydroxylase activities were not influenced by the betaine pretreatment. Betaine was shown not to affect any of the enzyme activities associated with glutathione (GSH) conjugation reaction, such as glutathione S-transferases (GSTs), glutathione disulfide (GSSG) reductase and GSH peroxidase irrespective of the time of its administration. When betaine was administered to mice 2-6 hr prior to sacrifice, hepatic GSH level, but not plasma GSH, was decreased significantly. Enhancement of the chloroform hepatotoxicity by betaine correlated well with the reduction in hepatic GSH levels. Both hepatic and plasma GSH levels were elevated in mice 24 hr following the betaine treatment. The results suggest that betaine affects induction of the chloroform hepatotoxicity by modulating the availability of hepatic GSH, which appears to be associated with its role in the transsulfuration pathway in the liver.
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PMID:Effects of singly administered betaine on hepatotoxicity of chloroform in mice. 973 16

Chloroform (CHCl3) and bromodichloromethane (BDCM) are generally the two most prevalent disinfection by-products formed during chlorination of drinking water, and both have been shown to be hepatotoxic, nephrotoxic, and carcinogenic in rodents. As the toxicity of these trihalomethanes (THMs) has most often been studied with corn oil as the vehicle of administration, the objectives of this study were to assess hepatotoxicity after exposure to single, low dosages of CHCl3 and BDCM given orally in an aqueous vehicle to estimate a lowest-observed-adverse-effect level (LOAEL) and a no-observed-adverse-effect level (NOAEL) and to compare toxic potency. Ninety-day-old male Fischer 344 rats were gavaged with either 0.125, 0.1875, 0.25, 0.5, 0.75, 1.0, or 1.5 mmol CHCl3 or BDCM/kg body weight in 10% Alkamuls EL-620 (5 ml/kg body weight). At 24 h postgavage, serum was collected for analysis of clinical chemistry indicators of liver damage. Both CHCl3 and BDCM induced dose-dependent hepatotoxicity; serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase were elevated significantly over control at 1.5, 1.0, and 0.5 mmol/kg. At these dose levels after 24 h, the two THMs appeared to be equipotent hepatotoxicants. Additional assessments at later time points demonstrated that BDCM causes more persistent liver damage than CHCl3 (Lilly et al., 1997). At 0.25, 0. 1875, and 0. 125 mmol of either THM/kg, significant increases over control were not detected for any measured endpoint. Therefore, these data indicate that the acute, oral NOAELs and LOAELs for liver toxicity are 0.25 and 0.5 mmol/kg, respectively, for both CHCl3 and BDCM. These determinations should provide a basis to establish new exposure limits for One-Day Health Advisories for these prevalent THMs.
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PMID:NOAEL and LOAEL determinations of acute hepatotoxicity for chloroform and bromodichloromethane delivered in an aqueous vehicle to F344 rats. 974 4

Clinical, clinico-pathological and serological studies were performed in sheep experimentally infected with Babesia ovis. Acute babesiosis occurred in all the lambs infested with adult Rhipicephalus bursa ticks and in one lamb infested with the larvae. The rate of parasitaemia and the degree of anaemia were not correlated. Decrease in the packed-cell volume ranged from 30 to 40%. Parasitized erythrocytes were not observed to block capillaries in the brain, which explained the absence of nervous symptoms in acute babesiosis. The kidneys were the most severely affected organs, exhibiting acute glomerulonephritis. The lesions observed were suggestive of vascular alteration and vascular stasis, leading to anoxia of the tissues. A disseminated intravascular coagulation (DIC) syndrome was recorded in sheep infected with babesiosis. A marked increase in the enzymes of the transaminase groups, mainly aspartate aminotransferase (AST), was observed. Enzymatic changes (increases in AST, alanine aminotransferase (ALT) and lactic dehydrogenase (LDH) and decreases in sorbitol dehydrogenase (SDH), alkaline phosphatase (ALP) and malic enzyme (MEZ)), decreases in total proteins and albumin, and increases in urea and creatinine might reflect the degree of severity of the damage to the liver and kidney tissues. Most of the lambs (85%) that were infested with larvae, and all lambs infested with adult R. bursa ticks, reacted serologically to B. ovis antigen. The serological reactions following infestation with the larvae occurred much later than those following infestation with the adult stage. The lambs which were infested with larvae showed mild clinical reactions when challenged by infected R. bursa adults, as compared with the reactions to the challenge in naive control animals. The serological findings, in addition to the fact that one splenectomized lamb reacted to larval infestation with acute ovine babesiosis, show that the preimaginal stages of R. bursa can transmit B. ovis, usually causing a sub-clinical disease. It is suggested that infections derived from preimaginal ticks in the winter can preimmunize sheep for the subsequent more severe infections derived from adult ticks in the summer. Furthermore, in the absence of a reliable vaccine against B. ovis, grazing flocks in the enzootic regions should be exposed to the preimaginal stages during their activity period (October-February) before exposure to the adult ticks in spring and summer (April-July).
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PMID:Clinical, clinico-pathological and serological studies of Babesia ovis in experimentally infected sheep. 978 Aug 25

The effects of orally administered dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene-dioxybiphenyl-2,2'-d icarboxylate (DDB) on the hepatotoxicity induced by carbon tetrachloride, acetaminophen or ethanol were investigated in rats and mice. Either single or repeated DDB pretreatment (50 or 200 mg/kg) did not alter the hepatotoxicity induced by carbon tetrachloride (0.2 or 1.0 ml/kg, i.p.) in female rats as indicated by increases in the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and sorbitol dehydrogenase (SDH) in serum. The hepatotoxicity of acetaminophen (350 mg/kg, i.p.) was also unaffected in male mice pretreated with DDB (50 mg/kg/d) for a week. However, DDB administration (50 mg/kg/d for 7 d) decreased the hepatic fatty degeneration induced by repeated ethanol treatment (0.75 g/kg, i.p., x2 times a day for a week) in rats as shown by the accumulation of triglycerides and cholesterol in the liver. Malondialdehyde (MDA) formation in liver homogenates was inhibited by DDB treatment. The significance of the action of DDB on alcoholic fatty liver generation in clinical settings is discussed.
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PMID:Effect of dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'- dicarboxylate (DDB) on chemical-induced liver injury. 998 71


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