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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A total of 300 female broiler chickens were reared from day-old to 10 d of age on the same starter diet. Then they were divided into five groups, receiving a control diet (Group 1) relatively rich in fat (14.3%) and unsaturated fatty acids (87.6%) and standardized with respect to vitamins and minerals, supplemented with 100 mg (Group 2) and 500 mg (Group 4) of RRR-alpha-,gamma-,delta-tocopheryl acetate/kg feed (40.6% alpha-, 41.1% gamma-, 18.3% delta-) or 100 mg (Group 3) and 500 mg (Group 5) all-rac-alpha-tocopheryl acetate/kg feed until slaughter at 6 wk of age. No differences between the supplemented groups were observed with respect to weight gain, feed consumption, packed cell volume (PCV), plasma enzyme activities of creatine kinase (CK) and glutathione peroxidase (GSH-Px), fatty acid composition, and enzyme activities of citrate synthase (CS), and total lactate dehydrogenase (LDH), and 3-OH-acyl-coenzyme A-dehydrogenase (HAD) of breast (Pectoralis major) and thigh (Gastrocnemius interna) muscle. Increasing levels of alpha-, gamma-, and delta-tocopherol were found in blood plasma with increasing dietary levels of these tocopherols. Only alpha-tocopherol was detectable in skeletal muscle and in higher concentrations in thigh than in breast muscle. Hemolysis in vitro and plasma activity of aspartate aminotransferase (ASAT) were lower (P < .01) in Groups 2 and 4 than in Groups 3 and 5. Interactions were observed between dietary type and concentration of tocopherols for plasma CK, GSH-Px, Na+, and K+. No measurable excretion of ethane and pentane was observed in any of the groups. The findings indicate that the oxidative stress in the live animals was minimal. The mixture of natural source RRR-alpha-,gamma-,delta-tocopherols was as efficient in protecting the live chickens as the all-rac-alpha-tocopheryl acetate, when provided on a weight basis as judged from the chosen in vivo parameters of vitamin E status.
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PMID:Supplementation of broiler diets with all-rac-alpha- or a mixture of natural source RRR-alpha-,gamma-,delta-tocopheryl acetate. 1. effect on vitamin E status of broilers in vivo and at slaughter. 882 89

1. Procaine has previously been shown to diminish the nephrotoxicity of cisplatin and the nephrotoxic effects of cisplatin and a new cisplatin complex (cis-diamminechloro-[2-(diethylamino) ethyl-4-aminobenzoate, N4]-chlorideplatinum (II) monohydrochloride monohydrate; DPR), that contains procaine hydrochloride were compared with rat renal cortical slices. 2. Cisplatin at 1 mM caused toxicity to the slices, as shown by an increase in the leakage of aspartate aminotransferase and lactate dehydrogenase from the slices into the incubation medium and a decrease in the reduction of a tetrazolium dye (MTT assay). Addition of procaine (1 mM) protected against cisplatin-induced toxicity. DPR either at 1 mM or at 4 mM had no effect either on the enzyme leakage or MTT reduction by the renal slices, but DPR at 10 mM produced a similar magnitude of enzyme leakage to cisplatin (1 mM). 3. DPR lowered the concentration of ATP and glutathione (GSH) in the slices but was less potent than cisplatin. Thiobarbituric acid reactive substances, indicators of lipid peroxidation, released into the medium were increased by the highest concentration of DPR (10 mM), which suggests that DPR has the potential to cause oxidative stress. 4. The results suggest that DPR was far less toxic than either cisplatin alone or a mixture of cisplatin and procaine.
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PMID:Comparison of the toxicities of cisplatin and a new cisplatin-procaine complex to rat renal cortical slices. 884 12

We found that NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) in rat liver cytosol reduces ubiquinone (UQ) to ubiquinol (UQH2) in lipid membranes and consequently inhibits lipid peroxidation [Takahashi T., et al., Biochem. J., 309, 883-890 (1995)]. Here we examined whether or not this UQH2-regenerating system functions as a cellular antioxidant defense in animals. Rats were given UQ-10 for 2 weeks, and were then exposed to carbon tetrachloride (CCl4). The UQ-10 supplement increased only in the NADPH-UQ reductase and the UQH2-10 pool of rat liver without any appreciable change in the levels of other antioxidant factors. On the other hand, CCl4 markedly increased plasma aspartate aminotransferase and alanine aminotransferase, liver weight and thiobarbituric acid reacting substances formation, which are indicators of CCl4-hepatitis, and it decreased the liver levels of L-ascorbic acid, reduced form of glutathione (GSH), alpha-tocopherol, NADPH-UQ reductase and glutathione S-transferase. However, all the above indicators of CCl4-induced hepatitis were significantly improved in rats given UQ-10. Furthermore, alpha-tocopherol, but neither L-ascorbic acid nor GSH, was significantly saved. UQ-10 supplement also was recovered glutathione S-transferase and NADPH-UQ reductase activities slightly. These results indicated that UQ-10 given to rats increased the cellular UQH2-10 pool and cytosolic NADPH-UQ reductase activity in their livers, resulting in the inhibition of lipid peroxidation in the biomembranes, and consequently protected the rats from the CCl4-hepatotoxicity.
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PMID:Cellular antioxidant defense by a ubiquinol-regenerating system coupled with cytosolic NADPH-dependent ubiquinone reductase: protective effect against carbon tetrachloride-induced hepatotoxicity in the rat. 887 5

Physiologically based pharmacokinetic modeling (PBPK) and gas uptake experiments have been used by researchers to demonstrate the competitive inhibition mechanism between trichloroethylene (TCE) and 1,1-dichloroethylene (DCE). Expanding on their work, we showed that this pharmacokinetic interaction was absent at levels of 100 ppm or less of either chemical in gas uptake systems. In this study, we further illustrate the presence of such an interaction threshold at the pharmacodynamic level by examining the interaction effect of either chemical on the other's ability to bind and deplete hepatic glutathione (GSH) in Fischer 344 rats. However, at this end point, the pharmacodynamic interaction is complicated by the ability of the liver to resynthesize GSH in response to its depletion. To quantitatively resolve the interaction effects on GSH content from the resynthesis effects, physiologically based pharmacodynamic (PBPD) modeling is applied. Initially, the PBPD model description of hepatic GSH kinetics was calibrated against previously published data and by gas uptake experiments conducted in our laboratory. Then, the model was used to determine the duration of the gas uptake exposure experiments by identifying the critical time point at which hepatic GSH is at a minimum in response to both chemicals. Subsequently, gas uptake experiments were designed following the PBPK/PD model predictions. In these model-directed experiments, DCE was the only chemical capable of significantly depleting hepatic GSH. The application of TCE to the rats at concentrations higher than 100 ppm obstructed the ability of DCE to deplete hepatic GSH. Since the metabolites of DCE bind to hepatic GSH, this obstruction signaled the presence of metabolic inhibition by TCE. However, TCE, at concentrations less than 100 ppm, was not effective in inhibiting DCE from significantly depleting hepatic GSH. The same observations were made when the ability of DCE to cause hepatic injury, as measured by aspartate aminotransferase serum activity, was assessed. Both conclusions validated the previous findings of the presence of the interaction threshold at the pharmacokinetic level.
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PMID:Physiologically based pharmacodynamic modeling of an interaction threshold between trichloroethylene and 1,1-dichloroethylene in Fischer 344 rats. 891 84

Hepatic cytokine gene expression is independently stimulated by circulating microbial products and reductions in the cellular O2 supply. Although these stimuli occur sequentially after gram-negative bacteremia, it is unknown whether their interplay augments production of interleukin (IL)-1 by the liver. We studied the effects of intraportal Escherichia coli (EC) bacteremia and secondary constant-flow hypoxia (Po2, approximately 46 Torr for 30 min) on IL-1 alpha and IL-1 beta gene expression in ex situ buffer-perfused rat livers over 180 min (n = 67). At t = 0, normoxic EC and normal saline (NS) controls received 10(9) live EC serotype 055:B5 and 0.9% NaCl, respectively; in livers subjected to EC+hypoxia-reoxygenation (H/R) and NS+H/R, hypoxia began 0.5 h after EC or NS and was followed by 120 min of reoxygenation. Portal and hepatic venous perfusates were serially analyzed for bacterial colony-forming units, O2 uptake, and aspartate aminotransferase. At 60 min (peak hypoxia) and 180 min, cDNAs for IL-1 alpha and IL-1 beta were hybridized to whole liver RNA, and IL-1 beta protein levels in venous perfusates were assessed. Intrahepatic levels of reduced glutathione (GSH) were measured as an index of oxidative stress. Compared with normoxic EC, IL-1 alpha transcripts decreased at 180 min in EC+H/R livers (P < 0.0001) as did IL-1 beta mRNA (P < 0.05), despite similar EC clearance, GSH levels, posthypoxic O2 uptake, and aspartate aminotransferase release. Hepatic secretion of IL-1 beta likewise fell in EC+H/R vs. EC controls (P < 0.005). Prostaglandin H synthase-2 (COX-2) message accumulation was not enhanced by H/R, and indomethacin did not reverse H/R-mediated suppression of IL-1 production. In contrast, H/R-related falls in EC-induced IL-1S expression were reversed by allopurinol or catalase. Thus brief hypoxic stress of the liver causing neither GSH depletion nor functional impairment downregulates postbacteremic IL-1 expression by a mechanism involving O2 radicals but not cyclooxygenase metabolites.
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PMID:Brief hypoxic stress downregulates E. coli-induced IL-1 alpha and IL-1 beta gene expression in perfused liver. 894 69

Cytochrome P450 2E1 (P450 2E1) is active in both the detoxification and activation of small organic molecules. The effects of 2-(allylthio)pyrazine (2-AP) on P450 2E1-catalytic activity and the expression of rat hepatic P450 2E1 were examined. 2-AP competitively inhibited 4-nitrophenol hydroxylase activity in vitro (Ki, 12 microM). 2-AP treatment of rats (200 mg/kg/day, p.o., 1-3 days old) resulted in 20-30% decreases in the rates of P450 2E1-specific metabolic activities. Immunoblot analysis also revealed that hepatic microsomes isolated from 2-AP-treated rats showed substantial decreases in P450 2E1 level. 2-AP-suppressed isoniazid (INH)-inducible hepatic P450 2E1 levels, as shown by both metabolic activities and immunoblot analyses. Thus, 2-AP was effective in suppressing both constitutive and inducible P450 2E1 expression. Northern blot analysis showed that 2-AP transiently suppressed the hepatic P450 2E1 mRNA level, suggesting that suppression in P450 2E1 expression by 2-AP may be mediated in part by transcriptional inactivation. Hepatoprotective effects of 2-AP against toxicants were monitored in mice. 2-AP pretreatment prior to the administration of lethal doses of acetaminophen (AAP) or INH substantially reduced toxicant-induced mortality. Whereas serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were markedly elevated after AAP administration (i.e. 9-20-fold), 2-AP pretreatment of animals before AAP administration resulted in >95% decreases in elevated serum aminotransferase activities. 2-AP was also effective against CCl4-induced hepatotoxicity. Whereas CCl4 treatment caused 35-70-fold increases in aminotransferase activities, treatment of mice with 2-AP (>10 mg/kg) resulted in the blocking of CCl4-induced liver toxicity. The hepatoprotective effect of 2-AP was in part due to 2-AP-induced elevation of hepatic GSH levels. Whereas AAP or CCl4 treatment resulted in 70-80% reduction in hepatic GSH levels, pretreatment of mice with 2-AP caused a 40-210% elevation in hepatic GSH levels, as compared with either AAP or CCl4 alone. 2-AP pretreatment also reduced AAP- or CCl4-induced increases in lipid peroxidation in a dose-dependent manner. The results of these metabolic activities and of immunoblot and RNA blot analyses demonstrate that 2-AP is efficacious in suppressing constitutive and inducible P450 2E1 expression and effective in protecting against toxicant-induced liver toxicity.
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PMID:Inhibition of cytochrome P450 2E1 expression by 2-(allylthio)pyrazine, a potential chemoprotective agent: hepatoprotective effects. 906 29

Morphological and biochemical changes in mitochondrial have been reported early in the course of cocaine-induced hepatotoxicity. This study was designed to examine the effects of repeated cocaine exposure in vivo on mitochondrial respiration, activities of respiratory chain enzymes, and lipid peroxide measures in liver. Male Sprague-Dawley rats were exposed to cocaine (5 i.p. injections of 25 mg/kg; 3-day period). Blood and liver samples were taken, and hepatic mitochondria were isolated by differential centrifugation. The cocaine-treated rats developed oxidative stress in hepatic mitochondria as evidenced by a significant increase in malonaldialdehyde (MDA; 52%; p < 0.0001) and a decreased glutathione (GSH; 22%; p < 0.0003). Blood aspartate aminotransferase (AST) and glutathione s-transferase (GST) levels in cocaine groups were significantly elevated (2.6 and 3.2 fold, respectively; p < 0.0001 for both). Cocaine caused a decrease in state-3 respiration and respiratory control ratio (RCR) ratio when exposed to site I and II substrates; these changes were parallelled by a decrease in complex I (22%; p < 0.003), succinate cytochrome c reductase (27%; p < 0.004), and complex IV (24%; p < 0.003). In conclusion, functional abnormalities of hepatic mitochondria accompany lipid peroxidation caused by cocaine, supporting the hypothesis that the mitochondria is one of the major intracellular targets of cocaine hepatotoxicity.
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PMID:Impairment of mitochondrial respiration and electron transport chain enzymes during cocaine-induced hepatic injury. 907 24

This study examines the effects of three calcium channel blockers (verapamil, nifedipine and diltiazem) on isolated rat hepatocytes exposed to ethanol. In the first part of our study, hepatocytes were incubated with increasing concentrations of ethanol (100, 300, 500, 1000 mM) for varying times. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) release were measured to evaluate the cytotoxic effects of ethanol. The concentration of 300 mM and time of incubation of 45 min were chosen for cytoprotection experiments in which calcium channel blockers, at two different concentrations, were added to the medium 30 min prior to the addition of ethanol. ALT, AST and LDH release as well as lipid peroxidation and cellular reduced glutathione (GSH) were measured. Nifedipine and verapamil (25 microM) reduced ALT, AST and LDH activities. The highest dose of diltiazem (50 microM) was more effective than the lowest one (25 microM). Ethanol caused a significant depletion of cellular GSH content as well as a moderate enhancement of lipid peroxidation. While none of the three calcium channel blockers was able to restore the decrease in GSH levels, diltiazem (25 microM) and nifedipine (50 microM) showed the greatest effect, significantly reducing lipid peroxidation.
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PMID:Hepatotoxicity of ethanol: protective effect of calcium channel blockers in isolated hepatocytes. 913 76

Hyperthermia has been used to treat cancer in the liver. However, significant hepatotoxicity occurs at a therapeutic temperature of 42-43 degrees C. We have proposed that heat toxicity is the result of oxidative stress from superoxide generation with resultant lipid peroxidation. Further, iron release from liver iron stores (ferritin) appears to play a central role in hyperthermic toxicity. In this study, rat livers were perfused in situ at 37 or 42.5 degrees C with and without deferoxamine for 1 h with an asanguinous perfusate. Oxidative stress was assessed by the efflux of glutathione (GSH) into the perfusage. Prior studies by Skibba et al. (1989a, 1991) showed that perfusage equivalents of GSH were primarily present as oxidized glutathione (GSSG). Lipid peroxidation was assessed by the measurement of aldehydes appearing in the perfusate and formation of hydrocarbon gases (ethane and pentane) in the perfusion chamber head space. Liver injury was assessed by the leakage of cytosolic enzymes, AST and LDH, into the perfusate. Livers perfused at 42.5 degrees C showed significant rises (p < 0.05) in AST and LDH after 60 min of perfusion but perfusion at 42.5 degrees C with deferoxamine added, was not significantly different from perfusion at 37 degrees C. Perfusion at 42.5 degrees C caused an increase in GSH into the perfusate at a level significantly (p < 0.05) greater than at 37 degrees C. GSH levels in the liver after 60 min of perfusion decreased from 4.82 +/- 0.76 microM/gm at 37 degrees C to 1.48 +/- 0.54 microM/gm at 42.5 degrees C (p < 0.05) but only fell to 3.42 +/- 1.23 microM/gm at 42.5 degrees C with deferoxamine added. Efflux of iron into the perfusate increase significantly with time and temperature. Low molecular weight chelated iron within the liver after perfusion increased from 5.88 +/- 1.46 nM/gm at 37 degrees C to 25.8 nM/gm at 42.5 degrees C (p < 0.05). Perfusate total aldehyde levels increased from 0.085 +/- 0.056 to 0.32 +/- 0.09 microM/ml after 60 min at 37 degrees C and 0.87 +/- 0.45 to 2.01 +/- 0.90 microM/ml at 42.5 degrees C (n = 8). There was a significant decrease in total aldehyde levels at 42.5 degrees C with the addition of deferoxamine to the perfusate, 0.36 +/- 0.14 to 0.86 +/- 0.27 microM/ml, when compared to 42.5 degrees C levels (p < 0.05). Levels of ethane and pentane in the perfusion chamber head space showed no significant changes with time or temperature of perfusion. The data suggest that lipid peroxidation may play a causal role in hyperthermia induced liver toxicity and that iron plays a major role in this injury. Failure of hydrocarbon analysis to support this conclusion appears related to the use of membrane oxygenators.
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PMID:Liver hyperthermia and oxidative stress: role of iron and aldehyde production. 914 47

Effects of acute physical exercise on the acetaminophen-induced hepatotoxicity were examined in adult female rats. Rats were forced to move at a speed of 10 m/min for 2 hr in a rotating cage. Immediately following the exercise bout rats were treated with acetaminophen (APAP; 700 mg/kg, i.p.). The physical exercise enhanced the hepatotoxicity of APAP as shown by increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities measured 24 hr following the treatment. A significant decrease in hepatic glutathione (GSH) was observed in the rats forced to exercise suggesting that the enhancement of APAP hepatotoxicity was associated with the depression of this endogenous tripeptide. The role of adrenergic stimulation in the exercise-induced hepatic GSH depression was examined by pretreating the animals with a receptor specific adrenergic antagonist, such as prazosin HCl (15 mg/kg, i.p.), propranolol HCl (15 mg/kg, i.p.), and yohimbine HCl (15 mg/kg, i.p.) 15 min prior to the exercise bout, but neither of the antagonists prevented the GSH depression. Administration of alpha-tocopherol acetate (450 mg/kg/day for 3 days and 150 mg/kg on day 4, i.p.) did not affect the exercise-induced GSH depression or lipid peroxidation in liver homogenates as determined by increases in malondialdehyde formation. These results suggest that neither adrenergic stimulation nor oxidative stress plays a significant role in the enhancement of APAP hepatotoxicity and hepatic GSH depression induced by acute physical exercise.
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PMID:Potentiation of acetaminophen hepatotoxicity by acute physical exercise in rats. 917 66


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