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

The effect of ethanol on the initiation of diethylnitrosamine- (DEN) induced liver carcinogenesis was investigated in rats. In the first experiment, eight-week-old male Wistar rats were maintained on four liquid diets: a basal diet (Group 1), a low-carbohydrate (low-CHO) diet (Group 2), a basal diet+ethanol (Group 3), or a low-CHO diet+ethanol (Group 4). After three weeks on these diets, 50 mg/kg of DEN was injected intraperitoneally. The plasma glutamic-oxaloacetic transaminase activity in Group 4 was higher 24 hours after DEN administration than in Groups 1 and 3. The plasma glutamic-pyruvic transaminase activity in Groups 3 and 4 was higher than in Groups 1 and 2. The number of gamma-glutamyltranspeptidase-positive foci per unit liver area 41 weeks after DEN administration was higher in Group 4 than in Group 1. The area of gamma-glutamyltranspeptidase-positive foci was greater in Groups 2 and 4 than in Group 1. In the second experiment, Groups 1 and 4 were given DEN orally (25 or 75 mg/kg). Plasma glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase activities 24 hours after DEN administration were significantly higher in Group 4 than in Group 1, but only when the dose of DEN was 75 mg/kg. In contrast, the number and area of placental glutathione S-transferase-positive foci per unit liver area were greater in Group 4 than in Group 1 only after 25 mg/kg of DEN. Thus the severity of hepatotoxicity and the incidence of precancerous liver lesions were not necessarily correlated. These findings together indicate that a combination of ethanol and a low-CHO diet enhances DEN-induced liver carcinogenesis in rats by increasing the bioactivation of DEN in the liver.
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PMID:Ethanol ingestion combined with lowered carbohydrate intake enhances the initiation of diethylnitrosamine liver carcinogenesis in rats. 135 84

1. Aflatoxin B1 (1.5 mg/kg body weight, i.p.) was administered to rats, mice, quail and chickens to examine the comparative effect on hepatic microsomal drug-metabolizing enzymes, cytosolic glutathione S-transferase and serum enzymes. 2. Administration of aflatoxin B1 to rats resulted in a significant decrease in microsomal cytochrome P-450, NADPH-cytochrome c reductase, activities of aminopyrine N-demethylase, aniline hydroxylase, cytosolic glutathione S-transferase and liver glutathione content. However, no significant changes in these parameters were seen in mice. 3. Quail showed a significant decrease in the content of cytochrome P-450 and the activities of aminopyrine N-demethylase, aniline hydroxylase and cytosolic glutathione S-transferase. A similar treatment did not affect these biotransformation enzymes in chickens. 4. The activities of serum enzymes, sorbitol dehydrogenase, alanine aminotransferase and aspartate aminotransferase were increased significantly in rats and quail. Mice exhibited a significant increase in the activities of sorbitol dehydrogenase and aspartate aminotransferase, while chickens showed a significant increase only in alanine aminotransferase.
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PMID:Comparative assessment of the effect of aflatoxin B1 on hepatic dysfunction in some mammalian and avian species. 135 19

The disposition of bromosulfophthalein was studied in chronically bile duct obstructed rats. In this model a catheter was inserted into the common bile duct and the distal tip was sealed. Resumption of bile flow was achieved with great ease. Obstruction of bile duct for 18 days in rats resulted in elevated bilirubin, ALT, AST, and alkaline phosphatase levels. Portal hypertension developed within this period (11.6 +/- 0.5 in obstructed rats vs. 8.6 +/- 0.6 mm Hg in sham-operated group). After the bile duct obstruction was opened, the half-life time for elimination of bromosulfophthalein (42.30 +/- 6.47 min) was longer than in sham-operated rats (21.23 +/- 3.34 min). Plasma clearance was reduced by 70% in bile duct obstructed rats. In spite of increased bile flow rate, biliary excretion of the dye was reduced by 40% in chronically bile duct obstructed rats. Hepatic glutathione levels were significantly reduced by 20% in this model. The specific activity of glutathione S-transferase with chlorodinitrobenzene and styrene oxide, as substrates, was reduced by 50% and 30%, respectively. However, the percent of conjugated bromosulfophthalein in bile was similar to that of sham-operated rats.
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PMID:Bromosulfophthalein disposition in chronically bile duct obstructed rats. 150 59

To assess the effect of prolonged administration of midazolam or isoflurane on hepatocellular integrity, we measured the concentrations of glutathione transferase (EC 2.5.1.18) B1 subunit and the activities of alanine aminotransferase (ALT; EC 2.6.1.2) and aspartate aminotransferase (AST; EC 2.6.1.1) in 40 patients who required long-term sedation with low-dose midazolam or isoflurane. Blood samples were collected before and 24 h after the start of the sedation and 0, 24, 72, 120, and 172 h after the last dose. ALT and AST activities did not change appreciably, but the glutathione transferase B1 concentration decreased significantly (P less than 0.03) at all times studied. The patients who received isoflurane and those who received midazolam showed no significant differences in any of the enzyme tests. We conclude that long-term sedation with midazolam or isoflurane is unlikely to affect hepatocellular integrity.
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PMID:Aspartate aminotransferase, alanine aminotransferase, and glutathione transferase in plasma during and after sedation by low-dose isoflurane or midazolam. 156 9

The effects of crocetin pretreatment on both hepatic aflatoxin B1 (AFB1)-DNA binding and AFB1 hepatotoxicity in rats has been examined. For these studies, male Wistar rats were treated with AFB1 (2 mg/kg) by i.p. administration, and the different degrees of hepatic damage were revealed by the elevations of levels of serum marker enzymes such as aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and gamma-glutamyltranspeptidase. After pretreatment of the animals with crocetin (2 or 6 mg/kg) daily for three consecutive days, the enzyme elevations were significantly suppressed. This suggested that the crocetin possessed chemopreventive effects on the early acute hepatic damage induced by AFB1. Under these experimental conditions, consistent elevations of hepatic glutathiones (GSH) and activities of glutathione S-transferase (GST) and glutathione peroxidase (GSH-Px) were observed. Crocetin treatment also decreased AFB1-DNA adduct formation in AFB1-treated animals. From these results, we suggest that the protective effect of crocetin on AFB1 hepatotoxicity in rats might be due to the hepatic tissues' defense mechanisms that elevated the cytosol GSH and the activities of GST and GSH-Px.
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PMID:Effects of crocetin on the hepatotoxicity and hepatic DNA binding of aflatoxin B1 in rats. 167 27

The effects of administration of dec-2-ynol and dec-2-ynoic acid on the hepatic glutathione (GSH) content and hepatic microsomal trans-2-enoyl-CoA reductase activity were examined in rat. Both compounds, when administered ip, caused a marked depletion of GSH levels and a corresponding inactivation of trans-2-enoyl-CoA reductase activity in both a time- and dose-dependent manner. The dec-2-ynoic acid caused greater hepatotoxicity than dec-2-ynol based on serum alanine transaminase activity. Based on the observations that (a) the alcohol did not interact with GSH in the presence or absence of cytosol, (b) the spectral manifestation of the interaction between GSH and the alcohol occurred only when NAD+ was added to the reaction mixture containing the cytosol and reactants, and (c) a similar absorbance spectrum was obtained following the interaction between aldehyde and GSH, it was concluded that dec-2-ynol is converted to an electrophile, dec-2-ynal, which causes depletion of GSH. The decrease in GSH content following administration of the acid appears to be due to activation of the acid to the electrophile, dec-2-ynoyl CoA, which then interacts with GSH, resulting in its depletion, based on the in vitro observations that (a) the acid did not interact with GSH in the presence or absence of cytosol, and (b) the spectral manifestation of interaction between GSH and dec-2-ynoyl CoA occurred both nonenzymatically and enzymatically in the presence of rat liver glutathione S-transferase (Sigma). Bovine serum albumin stimulated the enzymatic reaction. Comparable to the effects on GSH were the effects of dec-2-ynol, dec-2-ynal, dec-2-ynoic acid, and dec-2-ynoyl CoA on the microsomal trans-2-enoyl-CoA reductase activity in vitro. While the alcohol had no effect on the enzyme activity, its electrophilic product, the aldehyde, was a potent inhibitor. Similarly, the acid did not inhibit the enzyme activity unless the acid was present at high concentration; however, its electrophilic product, the CoA thioester, was a very potent inhibitor at very low concentration.
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PMID:Depletion of rat hepatic glutathione and inhibition of microsomal trans-2-enoyl-CoA reductase activity following administration of a dec-2-ynol and dec-2-ynoic acid. 173 41

Our objective was to determine if the previously reported protective effect of hypothyroidism against 1,1-dichloroethylene hepatotoxicity was associated with a change in distribution and covalent binding. Sprague-Dawley male rats were made hypothyroid (HypoT) by surgical thyroidectomy 2 weeks prior to studies and compared to euthyroid (EuT) rats. Hypothyroidism decreased body weights and liver to body weight ratios while mitochondrial non-protein sulfhydryl groups and cytosolic alcohol dehydrogenase activities were increased by 50%. Rats received a single oral dose of 100 mg [14C]1,1-dichloroethylene (DCE)/kg in mineral oil and were killed at 2, 4, 12 or 24 h; controls received mineral oil only. More rapid liver injury, as measured by serum alanine aminotransferase activity and histology, was present at 2 and 4 h after DCE in HypoT than EuT rats, but a similar magnitude of injury was evident at 12 and 24 h. DCE decreased liver non-protein sulfhydryl groups to a comparable extent in HypoT and EuT rats. Cytosolic glutathione S-transferase and alcohol dehydrogenase activities were decreased only in HypoT rats after DCE. HypoT rats excreted approximately 30% less total [14C]DCE-derived label in urine and their livers, kidneys and lungs consistently contained slightly less covalently bound [14C]DCE-derived label. In contrast, between 1 and 4 h after DCE, greater amounts of acid-soluble and acid-precipitable [14C]DCE-derived label were recovered in red blood cells of HypoT rats. Our results indicate that hypothyroidism did not protect against oral DCE hepatotoxicity but was associated with a more rapid injury at early times. Concurrently, hypothyroidism was found to change the fate of [14C]DCE with higher amounts of 14C-label recovered at early times in red blood cells while less 14C-label was excreted in urine and bound to liver.
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PMID:1,1-Dichloroethylene hepatotoxicity: hypothyroidism decreases metabolism and covalent binding but not injury in the rat. 176 16

The effect of bucillamine (BA) on glutathione (GSH) and GSH-related enzymes was investigated in C57 mouse. Administration of high doses of BA (150-400 mg/kg) produced a dose-dependent depletion (20-44%) of hepatic GSH, which was similar in magnitude to that produced by equimolar doses of other sulphydryl drugs studied previously. GSH depletion after acute BA administration correlated well with the elevation of serum glutamic-pyruvic transaminase (SGPT) (6-9-fold increase above control). The increase in SGPT after chronic administration (7 days), although significantly higher than the controls, was however much less than after acute administration. The hepatic GSH concentrations of mice given 7 days of BA were similar to the controls, again correlating well with SGPT activity. Administration of BA (150-400 mg/kg) caused also a significant dose-dependent increase in the oxidized glutathione (GSSG) in blood by 2-7-fold, as well as a dose-dependent increase in blood glutathione S-transferase (GST) activity (2-13-fold). In an in vitro experiment, hepatic GST activity was activated by various concentrations of BA (1 microM-1mM). There was little or no effect on GSSG reductase and on glutathione peroxidase (GSH-Px) after acute administration of BA. Chronic administration of BA had no effect on hepatic GSSG reductase and GSH-Px, but GSSG reductase activity in blood was increased significantly by 4-fold. It is possible that BA may affect the redox status through auto-oxidation and oxidation with endogenous thiols such as glutathione, affecting GSH concentrations and the GSH/GSSG ratio in tissues and, thus, having both metabolic and toxicological consequences. Whether or not the induction of GST activity in vivo in blood and in vitro in liver enzyme preparations shared the same underlying mechanism(s) requires further investigation.
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PMID:The effects of bucillamine on glutathione and glutathione-related enzymes in the mouse. 186 40

In the companion paper we demonstrated that hepatic vitamin E in rats becomes depleted and extrahepatic pools of vitamin E are altered by treatment with 1,2-dibromoethane (DBE). Vitamin E depletion may be dependent upon initial steps of DBE metabolism that are either oxidative (cytochrome P450 dependent) or conjugative (glutathione transferase dependent). That the liver content of glutathione (GSH) and vitamin E, the plasma concentration of vitamin E, and the serum activities of AST and ALT may be influenced by cytosolic metabolism of DBE was assessed by comparison of findings from rats treated with either 1,2-dichloroethane (DCE) or 1-bromo-2-chloroethane (BCE). The extent of oxidative metabolism was diminished by the use of tetradeutero-DBE (d4-DBE), and the availability of GSH for conjugative metabolism was diminished by pretreatment of rats with L-buthionine-S,R-sulfoximine (BSO) prior to treatment with DBE. Our results indicate that neither DCE nor BCE provokes a liver vitamin E depletion in rats, that d4-DBE treatment hastens but does not enhance the observed hepatic vitamin E depletion by comparison to animals treated with an equimolar dose of DBE, and that BSO pretreatment prevented the hepatic vitamin E depletion observed from animals treated with DBE alone. These results indicate that hepatic vitamin E depletion is the unique sequelae to conjugation of GSH with DBE, and we suggest the reactive episulfonium ion intermediate or a macromolecular adduct of this ion derived from DBE may play a role in liver vitamin E depletion associated with exposure to DBE.
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PMID:Modification of hepatic vitamin E stores in vivo. III. Vitamin E depletion by 1,2-dibromoethane may be related to initial conjugation with glutathione. 189 41

Acetaminophen (APAP)-induced cytotoxicity and metabolism were studied in hepatocyte cultures isolated from the rat, rabbit, dog, and monkey. Cytotoxicity was evaluated by morphological examination and by alanine aminotransferase and aspartate aminotransferase released into the cell culture medium. The toxicity results obtained by these two methods were in agreement and can be explained by the biotransformation of APAP in each species. Rat and dog hepatocyte cultures contained the most APAP-sulfate conjugates, while the rabbit, dog, and monkey hepatocyte cultures contained the most APAP-glucuronide conjugates. The percentage of APAP-glutathione conjugate was very low in all species, indicating that either very little of the toxic APAP metabolite, N-acetylbenzoquinoneimine, was formed, or in the species susceptible to N-acetylbenzoquinoneimine-induced cytotoxicity, the glutathione S-transferase activity or the amount of glutathione was low. Rabbit hepatocytes transformed the most APAP during both short and long periods of exposure. Of the four species, the dog hepatocytes exhibited the highest level of APAP-induced cytotoxicity. The sensitivity of dog hepatocytes to APAP may be due to their low conjugating enzyme activity. Rat hepatocytes utilized all three pathways of APAP-biotransformation to prevent APAP-induced cytotoxicity. Monkey hepatocyte cultures had a very large capacity to transform APAP to a glucuronide conjugate and a very high level of glutathione S-transferase activity, and therefore did not exhibit any cytotoxicity. These studies indicate that the competing pathways of APAP conjugation in hepatocyte cultures from different species explain the differences observed in APAP-induced cytotoxicity.
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PMID:Metabolism and cytotoxicity of acetaminophen in hepatocyte cultures from rat, rabbit, dog, and monkey. 198 16


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