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)

Mercury is the major component of dental amalgam restorative material, which typically has 50% pure elemental mercury. It is also used in some skin creams, and in the manufacturing of plastic, drugs and fungicides. The present study was designed to investigate the toxicity of methyl mercury (MeHg+) on isolated rat hepatocytes using several toxicity parameters. The hepatocytes were isolated by a collagenase perfusion technique and were incubated with different concentrations of MeHg+ (0.1-100 ppm) for 2 h. Through the incubation period the viability was determined by Trypan blue exclusion. Reduced glutathione (GSH) content and its enzymes, glutathione peroxidase (GSH-PX) and glutathione reductase (GSH-RX) were measured. Leakage of enzymes such as aspartate transaminase (AST), and alanine transaminase (ALT) were determined. The cell viability was reduced significantly after 1 h incubation when 0.1 and 1 ppm MeHg+ were applied. The decrease in the cell viability was dose- and time-dependent. A depletion of GSH content was observed with 100 ppm MeHg+ after 30 min of incubation. A significant decrease in GSH-RX was observed with 100 ppm during 15 and 30 min of incubation, while 10 ppm of MeHg+ significantly increased ALT leakage after 60 min. However, there was a significant increase in AST leakage with 100 ppm only. The present investigation indicates that the toxic effect of MeHg+ is most likely cytosolic enzyme related.
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PMID:The mechanism of methyl mercury toxicity in isolated rat hepatocytes. 835 70

1. Osbeckia octandra is a plant used in traditional medicine to treat jaundice and other liver disorders. In this study, the effects of Osbeckia leaf extract on paracetamol-induced liver injury were investigated both in vivo in mice and in rat hepatocytes in vitro. 2. Oral administration of Osbeckia extract (330 mg/kg) at the same time as paracetamol (450 mg/kg) to mice, resulted in a significant protection (p < 0.05) against liver damage, as assessed by improvements in the blood Normotest (39.1 +/- 1.9 versus 46.3 +/- 2.0 s), total liver glutathione (730 +/- 39 versus 574 +/- 27 micrograms/250 mg liver), plasma aspartate aminotransferase level (916 +/- 225 versus 1965 +/- 291 iu/l), and liver histopathology at 24 h after paracetamol administration. 3. In experiments to assess the direct effects of Osbeckia extract, significant protection was also found in freshly isolated rat hepatocytes against damage induced by 185 microM 2,6-dimethyl N-acetyl p-quinoneimine (2,6-diMeNAPQI, an analogue of NAPQI, the toxic metabolite of paracetamol) in vitro. When Osbeckia extract (500 micrograms/ml) was added to the incubation medium at the same time as 2,6-diMeNAPQI significant changes in cell viability (78.4 +/- 3.3 versus 47.2 +/- 5.8% of control, p < 0.001), cell reduced glutathione (GSH) level (35.0 +/- 3.1 versus 23.8 +/- 1.5%, p = 0.009), and reduced release of lactate dehydrogenase (129.9 +/- 6.6 versus 224.6 +/- 12.1%, p < 0.001) were demonstrated after 1 h incubation as compared with 2,6-diMeNAPQI alone. 4. Significant protection was still obtained against 2,6-diMeNAPQI in vitro when addition of Osbeckia extract was delayed by 20 min. These results indicate that Osbeckia extract can protect against paracetamol-induced liver injury.
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PMID:Protective effects of Osbeckia octandra against paracetamol-induced liver injury. 855 82

The contribution of testosterone to the nephrotoxic effects of 1,2-dichloropropane (DCP) was assessed by a series of castration and sex hormone replacement experiments on Wistar rats. The nephrotoxic action of DCP was evaluated by measuring the accumulation of organic anion and release of aspartate aminotransferase into the incubation medium using a renal cortical slice model. Our data show that sex, castration, and testosterone pretreatment are factors that influence the effect of DCP on renal cortical slices of rats Males appear to be more sensitive to nephrotoxic effects of DCP than females, male castration prevents the nephrotoxic effects of DCP, and pretreatment of females and castrated males with testosterone increases the susceptibility to DCP. In this study an attempt was made to evaluate the role of sex differences in the expression of enzymes participating in Phase I and Phase II detoxication reactions in order to explain the differences in sensitivity of the two genders to the nephrotoxic action of DCP. Our results implicate gender-specific expression of cytochrome P-450 in the kidneys as a predominant factor that determines the different susceptibilities of male and female rats to the nephrotoxic effect of DCP. We propose that the oxidation of DCP by CYP IIE1 is the first saturable and limiting step in the metabolic activation of DCP to nephrotoxic metabolites. It appears that, despite the fact that the nephrotoxic effect of DCP is determined mainly by its cysteine-conjugated metabolites, gluthathione (GSH) content and glutathione S-transferase (GST) activity in kidney are not directly related to increased androgen-related susceptibility to DCP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of sex-related differences in nephrotoxicity of 1.2-dichloropropane in rats. 857 Aug 64

Propolis (bee glue) is one of the major hive products of bees and is rich in flavonoids, which are known for antioxidant activities. Doxorubicin-induced myocardiopathy is the consequence of oxidative stress through the mediation of free radicals. The effect of intraperitoneal administration of propolis (50 and 100 mg/kg) was studied on cardiomyopathy produced by doxorubicin (10 mg/kg, i.v.) in rats. Serum creatine phosphokinase (CK), aspartate aminotransferase (AST), blood and tissue glutathione (GSH), and thiobarbituric acid reactive substances (TBARS) in heart were estimated to assess the status of heart muscle. An elevation of the levels of CK, AST, GSH, and TBARS was observed following doxorubicin treatment. Parallel experiments with a pretreatment of propolis significantly reduced the levels of these parameters . Biochemical observations were supplemented by histopathological examination of heart sections. The protective effect of propolis was compared with that of rutin, a known cardioprotective flavonoid. The study demonstrates the cardioprotective effect of propolis in doxorubicin-induced experimental cardiotoxicity.
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PMID:Propolis protects against doxorubicin-induced myocardiopathy in rats. 861 23

The aim of this study was an experimental assessment of the influence of caffeine on the symptoms of the toxic action of paracentamol in mice as well as a detailed analysis if paracetamol pharmacokinetics in men receiving caffeine at the same time. The toxicologic investigations were performed in 620 Swiss mice. The LD50 and LD100 were determined after an administration of paracetamol intraperitoneally. The effects of two doses of caffeine on the survival time and number of animal deaths were investigated. The degree of hepatic damage was assessed on the basis of biochemical serum criteria, i.e. alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and concentration of bilirubin in serum, as well as on the basis of biochemical investigations of liver homogenates, estimating the concentration of reduced glutathione and P-450 cytochrome in the liver. The anatomicopathologic liver evaluation was also performed, including histological and histopathological examinations (glycogen, lipids). The pharmacological investigations were performed in 9 healthy volunteers in two randomized subgroups with the use of a cross-over method twice at one week intervals. The blood paracetamol level was determined according to the method of Thoma et al. The course of changes of paracetamol plasma levels was described with a one-compartment model for extravascular administration of the drug. The biexponential equation, describing the assumed model, was solved with the method of the smaller squares, using non-linear approximation. (Tab 1-6, Fig. 1-3). The experimental studies demonstrated a decrease in both the acute toxicity and hepatotoxic action of paracetamol administered in combination with caffeine, which was indicated by a significant decrease in aminotransferase and alkaline phosphatase activity and in concentration of bilirubin as well as by an increase in the concentration of P-450 cytochrome and GSH in the liver which decreased after administration of paracetamol alone and also by limitation or lack of hepatic necrosis. The pharmacokinetic calculations in men demonstrated an interaction between paracetamol and caffeine which was indicated by a decrease in plasma paracetamol levels, by a smaller surface under the curve of changes of paracetamol levels indicating faster elimination of the drug after simultaneous administration with caffeine. Therefore, paracetamol preparations with caffeine may be less toxic than paracetamol alone.
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PMID:[Influence of caffeine on toxicity and pharmacokinetics of paracetamol]. 861 54

The hepatotoxicity of acetaminophen overdose depends on the metabolic activation to a toxic reactive metabolite by the hepatic mixed function oxidases. There is evidence that an increase in cytosolic Ca2+ is involved in acetaminophen hepatotoxicity. The effects of the Ca2+-antagonists nifedipine (NF), verapamil (V), diltiazem (DL) and of the calmodulin antagonist trifluoperazine (TFP) on the activity of some drug-metabolizing enzyme systems, lipid peroxidation and acute acetaminophen toxicity were studied in male albino mice. No changes in the drug-metabolizing enzyme activities studied and in the cytochrome P-450 and b5 contents were observed 1 h after oral administration of V (20 mg/kg). DL (70 mg/kg) and TFP (3 mg/kg). NF (50 mg/kg) increased cytochrome P-450 content, NADPH-cytochrome c reductase and ethylmorphine-N-demethylase activities. DL and TFP significantly decreased lipid peroxidation. NF, V, DL and TFP administered 1 h before acetaminophen (700 mg/kg orally) increased the mean survival time of animals. A large increase of serum aspartate aminotransferase(AST), and liver weight and depletion of liver reduced glutathione (GSH) occurred in animals receiving toxic acetaminophen dose. NF, V and DL prevented and TFP decreased the acetaminophen-induced hepatic damage measured both by plasma AST and by liver weight. NF, V, DL and TFP changed neither the hepatic GSH level nor the GSH depletion provoked by the toxic dose of acetaminophen. This suggests that V, DL and TFP do not influence the amount of the acetaminophen toxic metabolite formed in the liver. The possible mechanism of the protective effect of NF, V, DL and TFP on the acetaminophen-induced toxicity is discussed.
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PMID:Effect of nifedipine, verapamil, diltiazem and trifluoperazine on acetaminophen toxicity in mice. 877 83

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


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