Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oleanolic acid (OA) is a triterpenoid compound that has been shown to protect against a number of hepatotoxicants, and is used in China to treat hepatitis. In the present study, we examined the effect of OA on acetaminophen (AA)-induced acute liver injury in mice and the mechanism(s) of protection. OA pretreatment (25-100 mg/kg s.c. for 3 days) remarkably decreased AA (500 mg/kg i.p.)-induced liver damage in mice, as indicated by decreased serum activities of alanine aminotransferase and sorbitol dehydrogenase, as well as by histopathological observation. Additionally, OA pretreatment mitigated AA (300-450 mg/kg i.v.)-induced depletion in liver glutathione (GSH) content. The protective effect was not evident until 24 hr after a single s.c. injection of OA (300 mg/kg) and lasted for 72 hr. To examine the mechanism of this protection, the biliary and urinary excretion of AA and AA metabolites were measured for 2 hr after AA administration (150 mg/kg i.v.) in bile duct-cannulated mice. OA pretreatment resulted in an increased urinary excretion of AA-glucuronide and a decreased biliary excretion of AA-GSH. Microsomes from OA-pretreated mice, incubated in vitro with AA, produced less benzoquinoneimine intermediate than controls, as determined by the formation of AA-GSH. Hepatic subcellular distribution of [3H] AA to the nuclear fraction was also decreased by OA. OA pretreatment of mice had no influence on liver UDP-glucuronic acid concentration, but increased hepatic glucuronosyltransferase activity toward AA. In summary, OA pretreatment dramatically protects against AA-induced hepatotoxicity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Protective effects of oleanolic acid on acetaminophen-induced hepatotoxicity in mice. 837 Nov 59

In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), thiabendazole (TBZ) causes renal injury characterized by an increase in serum urea nitrogen (SUN) concentration and by tubular necrosis. Previous studies have shown that TBZ requires metabolic activation before it produces nephrotoxicity and that the structure contributing to the toxicity of TBZ is the thiazole moiety of the molecule. TBZ and its thiazole analogues were examined for the ability to increase SUN concentration and serum alanine aminotransferase activity in GSH-depleted mice. Unsubstituted thiazole and thiazoles with 4- and/or 5-, and no 2-, substituents caused marked increases in SUN concentration, suggesting nephrotoxicity. Furthermore, the nephrotoxic potency of these thiazoles decreased with the increasing number and bulk of the 4- and/or 5-substituents. On the other hand, the target organ (the kidney or liver) and the toxic potency of 4-methylthiazoles were markedly altered with the type of substituents at the 2-position. These observations and the known toxicity of thiono-sulfur compounds led us to the hypothesis that the nephrotoxic thiazoles, which lack 2-substituents, would undergo microsomal epoxidation of the C-4,5 double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form thioformamide, a possibly toxic metabolite. Evidence for this hypothesis was provided by the results that thioformamide and tert-butylglyoxal as the accompanying fragment were identified as urinary metabolites in mice dosed with 4-tert-butylthiazole and that thioformamide caused a marked increase in SUN concentration when administered to mice in combination with BSO.
 ...
PMID:Possible role of thioformamide as a proximate toxicant in the nephrotoxicity of thiabendazole and related thiazoles in glutathione-depleted mice: structure-toxicity and metabolic studies. 847 8

Inhalation exposure to styrene at concentrations that cause metabolic saturation results in significantly greater hepatotoxicity in B6C3F1 mice than in Swiss mice; females of both strains are more susceptible than males. These studies were conducted to investigate the mouse strain and gender differences in susceptibility to hepatotoxicity caused by repeated exposure to styrene at concentrations that do not cause metabolic saturation. Male and female B6C3F1 and Swiss mice (8 weeks old) were exposed to 0, 150, or 200 ppm styrene for 6 hr/day, 5 days/week, for up to 2 weeks. Changes in body and liver weights, serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) levels, liver histopathology, and total liver glutathione (GSH) were evaluated after 2, 3, 5, and 10 exposures (six mice/sex/strain/time point/concentration). Blood levels of styrene and styrene-7,8-oxide (SO) were measured in mice exposed to 200 ppm styrene for 2,3, or 5 days (six mice/sex/strain/time point/concentration). Serum ALT and SDH levels were significantly elevated only in female B6C3F1 mice after 3 exposures to 200 ppm styrene; enzyme levels had returned to control levels when measured after 5 and 10 exposures. Degeneration and coagulative necrosis of centrilobular hepatocytes were observed in female B6C3F1 mice exposed 2, 3, and 5 days to 150 or 200 ppm styrene; incidences of these lesions were greater in the 200 ppm than in the 150 ppm dose group. After 10 days of exposure to 150 or 200 ppm styrene, hepatocellular lesions had resolved, although a residual chronic inflammation was present in livers of most female B6C3F1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Comparison of styrene hepatotoxicity in B6C3F1 and Swiss mice. 852 16

Sodium arsenite and cadmium chloride, were administered orally to adult female rats at 21 and 4 h prior to sacrifice. Liver, lung, skin and urinary bladder were the tissues studied. DNA damage, cytochrome P450, glutathione content (GSH), ornithine decarboxylase (ODC), serum alanine aminotransferase and heme oxygenase activity were measured. Sodium arsenite increased rat hepatic ODC activity at 1.6 and 24.6 mg/kg and hepatic heme oxygenase activity at 8.2 and 24.6 mg/kg, but did not cause any DNA damage. Cadmium chloride did not affect any of the six parameters tested. These findings suggest that sodium arsenite may be a promoter rather than an initiator of carcinogenesis.
 ...
PMID:Arsenite, but not cadmium, induces ornithine decarboxylase and heme oxygenase activity in rat liver: relevance to arsenic carcinogenesis. 855 13

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.
 ...
PMID:[Influence of caffeine on toxicity and pharmacokinetics of paracetamol]. 861 54

The hepatotoxicity of the 3 isomers of para-substituted thiobenzamides and the 3 isomers of 2-(para-substituted phenyl)-4-methylthiazoles was evaluated in mice depleted of glutathione (GSH) by pretreatment with buthionine sulfoximine (BSO). In accordance with previous studies with the rat, p-methoxythiobenzamide was more toxic than thiobenzamide, and conversely p-chlorothiobenzamide was markedly less toxic as assessed by serum alanine aminotransferase (ALT) activity. The hepatotoxicity of 2-phenyl-4-methylthiazole was also altered by the addition of para-substituents to the phenyl ring in the same way as observed for thiobenzamide derivatives: the rank order of toxicity was 4-methylthiazoles having p-methoxyphenyl > phenyl >> p-chlorophenyl at the 2-position. This good correlation of the rank order of hepatotoxicity between series of 2-(para-substituted phenyl)-4-methylthiazoles and para-substituted thiobenzamides supports the concept that thiobenzamides as ring cleavage metabolites play a role in the hepatotoxicity of 2-phenylthiazole derivatives.
 ...
PMID:Relative hepatotoxicity of 2-(substituted phenyl)thiazoles and substituted thiobenzamides in mice: evidence for the involvement of thiobenzamides as ring cleavage metabolites in the hepatotoxicity of 2-phenylthiazoles. 865 Jun 92

Hepatic levels of GSH and Phase II detoxication enzymes were compared to biochemical and histological indices of hepatic damage in 4- to 76-week-old nontransgenic mice and their transgenic littermates that overexpress the hepatitis B virus large envelope protein. The mice were fed a low-sucrose AIN-76A diet ad libitum. Hepatic-specific activities of quinone reductase (QR) and glutathione S-transferase (GST) were increased 2- to 10-fold beginning at 12 weeks of age in transgenic mice and correlated with increases in serum alanine aminotransferase (ALT) (r = 0.84 and 0.59, respectively). Quantitative histological analysis demonstrated that apoptosis was the predominant feature in 4- to 12-week-old transgenic mice, whereas necrosis and inflammation predominated at later time points. Surprisingly, 3-fold elevations in ALT were observed beginning at 52 weeks of age in nontransgenic mice, and hepatic-specific activities of QR and GST were also modestly increased in elderly nontransgenic animals. In contrast to transgenic mice, apoptosis was not a prominent feature. The strongest histological correlates to ALT in 4- to 76-week-old nontransgenic mice were necrosis and inflammation (r > 0.96), which in turn may have been evoked by hepatic fat accumulation. Profiles of specific GST isoforms were quantitated chromatographically and identified by sequencing tryptic digests. The Ya1 subunit of alpha-class GST was markedly increased from undetectable levels in transgenic mice, while more modest increases were observed in nontransgenic mice more than 1 year old. Fivefold elevations of the Yb1 subunit, a constitutively expressed mu-class GST, were found in transgenic mice older than 4 weeks of age, while 2-fold increases were observed in nontransgenic animals that were more than 1 year old. These studies demonstrate that selected increases in Phase II detoxication enzymes are a stereotyped response to chronic hepatitis that is strikingly reminiscent of the treatment of mice with anticarcinogenic enzyme inducers.
 ...
PMID:Elevations of hepatic quinone reductase, glutathione, and alpha- and mu-class glutathione S-transferase isoforms in mice with chronic hepatitis: a compensatory response to injury. 866 Jun 89

The influence of r-HuEPO on the activity of erythrocyte transketolase (ETKA), glutathione reductase (GSH) and glutamic-pyruvic transaminase (EGPT) was determined by spectrophotometry. 150 IU/kg BW/week of r-HuEPO was given i.v. during 2 months to 12 predialyzed uremics (PDU). Twenty healthy volunteers (HV) served as controls. GSH and EGPT activity were expressed as a coefficient. ETKA in HV = 2.39 +/- 0.10 and PDU = 1.53 +/- 0.10 mumol/ml/min differed significantly (p < 0.001). GSH in HV = 1.20 +/- 0.09 and PDU = 1.25 +/- 0.07, EGPT in HV = 1.20 +/- 0.10 and PDU = 1.38 +/- 0.11 differed significantly (p < 0.01 and p < 0.001, respectively). After 2 months of r-HuEPO treatment, ETKA, GSH and EGPT rose significantly (p < 0.01). Thus, r-HuEPO increases the activity of enzymes related with the content of vitamins B1, B2 and B6 in uremics.
 ...
PMID:Recombinant human erythropoietin improves enzyme activity in erythrocytes of predialysis uremics. 867 97

Effect of glutathione (GSH) depletion on paraquat (PQ) toxicity in the liver and kidneys of mice was examined. Glutamic-pyruvate transaminase (GPT) and blood urea nitrogen (BUN) levels in plasma of mice were hardly changed by treatment with 150 micro mol/kg of PQ. However, significant increases in the plasma GPT and BUN levels after PQ injection were observed in mice which were pretreated with L-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, at 4 hr prior to PQ administration. This result supports the previous observation that hepatotoxicity of PQ was enhanced in diethyl maleate-pretreated mice (Cagen and Gibson, 1977). In the present study, lipid peroxidation evaluated by thiobarbituric acid-reactive substances (TBA-RS) level in the liver of mice given PQ was elevated by pretreatment with BSO. Moreover, enhancement of PQ cytotoxicity by BSO pretreatment was also observed in cultured mouse hepatoma cell line (NCTC clone 1469). Vitamin E, an antioxidant, and Desferal, an iron chelator, significantly prevented mice from the BSO-enhanced hepato- and nephrotoxicity of PQ. These findings suggest that the tissues or cells of low GSH concentration are highly vulnerable to PQ toxicity and GSH may play a major role in diminishing the toxic action of PQ exerted through oxidative stress.
 ...
PMID:Enhancement of paraquat toxicity by glutathione depletion in mice in vivo and in vitro. 872 Jan 62

Glutathione (GSH) is the major intracellular antioxidant and is essential to normal cell function and replication. Cysteine and other thiol compounds have been considered rate-limiting for GSH biosynthesis, but recent studies have demonstrated that glutamine (GLN) becomes essential during metabolic stress to replete tissue GSH levels which have become depleted. To determine the role of GLN supplementation in the resting, nonstressed state, we studied three groups of Wistar rats. The animals were catheterized and randomly assigned to one of three groups; (1) chow ad libitum group receiving iv saline (control), (2) standard total parenteral nutrition (STA-TPN) group, and (3) glutamine-enriched TPN (GLN-TPN) group. The intravenously fed animals received no rat chow. The infusions were administered at a rate of 2.2 ml/hr for 4 days and all animals were harvested on the fifth day of study. The GLN-TPN group had a significantly higher plasma GSH level than STA-TPN or control animals (P < 0.01). The hepatic concentration of GSH and the oxidized GSH/reduced GSH were similar in all groups. GLN-TPN had a significantly lower plasma ALT level than the control group (P < 0.05). The control group had a significantly higher ALP level than STA-TPN and GLN-TPN animals (P < 0.01). There were no significant differences in other measures of hepatic functions among the three groups. Our data demonstrate that in this model GLN-enriched TPN enhances plasma GSH concentrations, while maintaining hepatic GSH stores. This suggests that GSH turnover is altered during glutamine-enriched TPN, which may explain how dietary GLN supplementation enhances tissue antioxidant capacity.
 ...
PMID:Glutamine-enriched total parenteral nutrition enhances plasma glutathione in the resting state. 876 39


<< Previous 1 2 3 4 5 6 7 8 9 10