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)

The ability of concurrent intraperitoneal injections of endotoxin (0.1 micrograms/kg) and galactosamine (700 mg/kg) to produce liver damage was determined in fasted C57Bl/6 mice of different ages: 2 months (young), 6 months (mature), and 24 months (aged). Liver damage was assessed after 6 hr by measurement of plasma alanine aminotransferase activity (ALAT, mumole/liter/min) and by histological examination for mature and aged mice. Control mice, those treated with saline, galactosamine, endotoxin, or hydrazine alone, had ALAT activities which ranged from 13 to 72 (n = 21). Plasma ALAT activities were increased to hepatotoxic values in some, but not all, mice injected with both endotoxin and galactosamine. For young mice, 7/11 had increased plasma ALAT activities; for mature mice, 5/8 had increased plasma ALAT activities and substantial centrilobular necrosis, whereas for aged mice, 0/7 had increased ALAT activities and none had centrilobular necrosis. Basophilic staining of the cytoplasm was increased by administration of endotoxin and/or galactosamine in both mature and aged mice whether or not necrosis was present. A 5-hr pretreatment with hydrazine sulfate (80 mg/kg) substantially decreased the ALAT release caused by endotoxin and galactosamine in mature mice. Hydrazine pretreatment prevented centrilobular necrosis in mature mice and decreased basophilic cytoplasmic staining in aged mice. The results demonstrate that aged mice are resistant to the hepatotoxic effects of endotoxin and galactosamine which were observed in both young mice and mature mice. Also, hydrazine sulfate pretreatment will protect against the hepatotoxic effects as well as the lethal actions of endotoxin and galactosamine.
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PMID:Aged mice are resistant to the hepatotoxic effects of endotoxin and galactosamine. 826 63

Plasma hyaluronan (HA) concentration and the rate of HA uptake by the isolated, perfused liver were measured in rats treated with saline, D-galactosamine (GaI-NH2, 50 mg/100 g body wt), gadolinium chloride (GdCl3) (0.5 mg/100 g body wt), and GdCl3 + GaI-NH2. GdCl3 was given 24 hr before GaI-NH2 or saline. Plasma L-alanine:2-oxoglutarate aminotransferase (EC 2.6.1.2), a marker for hepatocyte damage, was increased by 8 hr and remained elevated for 24 hr after GaI-NH2 injection. GdCl3 did not affect plasma enzyme levels when given alone or in association with, but prior to, GaI-NH2. Plasma HA levels were increased (200%) within 24 hr after GaI-NH2 administration. A plateau was reached at 8 hr, which was maintained for at least 24 hr. Although GdCl3 alone did not affect plasma HA levels, it slightly delayed the increase in HA concentration in GaI-NH2-treated rats. Livers, isolated 24 hr after GaI-NH2 treatment, exhibited a severe depression (approximately 67%) of HA uptake. GdCl3 did not prevent this suppression. The data presented indicate that: (1) one of the sinusoidal endothelial cell-dependent functions of the liver, i.e. removal of HA from the blood stream, is profoundly impaired during galactosamine-induced hepatitis, and (2) the adverse effect of GaI-NH2 on this sinusoidal endothelial cell function may not be dependent on CdCl3-suppressible Kupffer cell functions.
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PMID:Association of galactosamine-induced hepatitis in the rat with hyperhyaluronanaemia and decreased hyaluronan uptake by the isolated, perfused liver. 836 40

Picroliv, a standardized extract from the plant Picrorhiza kurrooa containing active constituents, showed a significant dose dependent (3-12 mg/kg p.o. x 7) protective activity against galactosamine-induced hepatic damage in rat as evaluated on the isolated hepatocytes (ex vivo) preparation. It markedly increased the percentage of viability of hepatocytes. It also restored the galactosamine-induced changes in the levels of enzymes (GOT, GPT and alkaline phosphatase) both in isolated hepatic cells as well as in serum. In addition, picroliv possessed a marked anticholestatic effect. Picroliv was found to be more potent than silymarin, a standard hepatoprotective agent.
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PMID:Prevention of galactosamine-induced hepatic damage by picroliv: study on bile flow and isolated hepatocytes (ex vivo). 844 80

Possible risks of fatal dacarbazine hepatotoxicity have not been studied systematically. We therefore asked whether dacarbazine hepatotoxicity is influenced by the dose or mode of application, by dacarbazine light-decay products, by prior liver damage or by an induction of dacarbazine metabolism. 22 Sprague-Dawley rats were treated with 4.5 mg and 200 mg dacarbazine/kg bodyweight i.p. and i.v., with dacarbazine light-decay products and with 4.5 mg and 200 mg dacarbazine/kg bodymass after previous galactosamine and ethanol treatment. Serum alanine aminotransferase, cholinesterase and white blood cell and platelet numbers were measured and liver histology was evaluated. Dose-dependent dacarbazine hepatotoxicity could be demonstrated by histology. The mode of application, dacarbazine light-decay products and acute liver damage did not influence dacarbazine hepatotoxicity. However 200 mg dacarbazine/kg bodymass after ethanol pretreatment caused significant serological changes and a significant leucodepression. The increased hepato- and myelotoxicity after induction of hepatic microsomal enzymes should be reason to exclude ethanol and drugs that induce hepatic microsomal enzymes prior to treatment with dacarbazine.
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PMID:Mechanisms of hepatotoxicity caused by dacarbazine in rats. 850 37

It is often assumed that at a younger age populations are at higher risk of toxic effects from exposure to toxic chemicals. Recent studies have demonstrated that neonate and postnatally developing rats are resilient to a wide variety of structurally and mechanistically dissimilar hepatotoxicants such as galactosamine, acetaminophen, allyl alcohol, and CCl4. Most interestingly, young rats survive exposure to the lethal combination of chlordecone (CD) + CCl4 known to cause 100% mortality in adult male and female rats. In a study where postnatally developing (20- and 45-day), and adult (60-day) male Sprague Dawley rats were used, administration of CCl4 (100 microliters/kg, i.p.) alone resulted in transient liver injury regardless of age as indicated by plasma alanine transaminase (ALT), sorbitol dehydrogenase (SDH) levels and histopathological lesions. In CD-pretreated rats, CCl4-induced toxicity progressed with time culminating in 25 and 100% mortality by 72 h after CCl4 in 45- and 60-day rats, respectively, in contrast to regression of CCl4-induced toxicity and 0% mortality in 20-day rats. [3H]Thymidine (3H-T) incorporation and proliferating cell nuclear antigen (PCNA) studies revealed an association between delayed and diminished DNA synthesis, unrestrained progression of liver injury, and animal death. Time-course studies revealed that the loss of resiliency in the two higher age groups might be due to inability to repair the injured liver rather than due to infliction of higher injury. Intervention of cell division in 45-day CD rats by colchicine (CLC, 1 mg/kg, i.p.) 30 h after CCl4 challenge increased mortality from 25 to 85%, confirming the importance of stimulated tissue repair in animal survival. In contrast, efficient and substantial DNA synthesis observed in 20-day rats allows them to limit further progression of liver injury, thereby leading to full recovery of this age group with 0% mortality. Examination of growth factors and proto-oncogene expression revealed a 3- and 3.5-fold increase in transforming growth factor-alpha (TGF-alpha) and H-ras mRNA expressions, respectively, coinciding with maximal hepatocyte DNA synthesis in 20-day normal diet (ND) rats, as opposed to only 2- and 2.5-fold increases observed in 60-day ND rats, respectively. Increased expression of c-fos (10-fold) in 20-day rats occurred 1 h after CCl4 compared to less than a 2-fold increase in 60-day rats. These findings suggest that prompt stimulation of tissue repair permits efficient recovery from injury during early postnatal development of rats.
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PMID:Efficient tissue repair underlies the resiliency of postnatally developing rats to chlordecone + CCl4 hepatotoxicity. 871 44

A novel experimental model of submassive liver necrosis with impaired regeneration has been established. A novel lipid A analogue, FS-112, was injected intravenously into male BALB/c mice, followed 2 days later by a 70% partial hepatectomy. Over the next 9 days, mice became severely jaundiced, with a peak total bilirubin (TBil) concentration of (mean +/- s.d.) 12.9 +/- 2.1 mg/dL 7 days postoperatively. In contrast, the TBil concentration in vehicle-treated mice remained less than 2 mg/dL. Significant elevations of L-alanine:2-oxoglutarate aminotransferase (ALT) were also observed 3-7 days after the operation in mice pretreated with FS-112, compared with mice pretreated with the vehicle. Submassive liver necrosis was observed with extensive mononuclear cell infiltration in mice treated with FS-112 and subjected to partial hepatectomy. Furthermore, both the BrdU and the proliferating cell nuclear antigen (PCNA) labelling index (LI) 1 day following partial hepatectomy in mice pretreated with FS-112 (8.6 +/- 4.3 and 7.9 +/- 4.2%, respectively) were significantly lower than levels in vehicle-treated mice (25.8 +/- 3.8 and 26.5 +/- 10.5%, respectively). The time course of changes in the BrdU LI in liver specimens from mice treated with both FS-112 and partial hepatectomy did not increase, even 3, 5, and 7 days postoperatively. Excellent liver regeneration with a PCNA LI 10-fold higher than the resting level was observed in mice treated with D-galactosamine hydrochloride. These results strongly suggest that this animal model of submassive liver necrosis may be suitable for clarifying the mechanisms of impaired liver cell regeneration often seen in fulminant hepatitis.
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PMID:Treatment with a novel lipid A analogue, FS-112, and partial hepatectomy causes submassive liver necrosis and impaired liver regeneration in mice. 874 20

The effects of dietary protein on the elevation of activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in D-galactosamine-injected rats were investigated. The rats fed with experimental diets containing test protein sources for 2 weeks were injected with D-galactosamine (0.8 g.kg-1 body weight). The activities of AST and ALT in serum were assayed after 20 h. According to the results, these enzyme activities in the rats fed 40% casein diet were higher than those of 5, 10, or 20% casein groups. In the 40% gluten group, these enzyme activities were lower than in the 40% casein group. This difference was not considered to be caused by the deficit of L-lysine and L-threonine in gluten. The extent of the reduction of UTP and UDP-glucose in liver by D-galactosamine was almost the same in the 40% gluten and 40% casein groups. These results suggest that levels and quality of dietary protein affect the susceptibility of animals to the hepatotoxin D-galactosamine and dietary gluten was found to alleviate the elevation of serum transaminases in rats by the drug.
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PMID:Dietary wheat gluten alleviates the elevation of serum transaminase activities in D-galactosamine-injected rats. 878 Sep 70

Carbamoylphosphate synthetase I (CPS I), a urea cycle enzyme, is located almost exclusively in the mitochondria of hepatocytes. The enzyme is unique in that it constitutes about 2-6% of total liver protein and is composed of a large subunit of 160 kD. We developed a sensitive enzyme-linked immunosorbent assay (ELISA) for measurement of the enzyme in plasma using an antibody against the rat enzyme. In galactosamine-induced rat acute hepatitis, plasma concentration of CPS I that was 1-2 micrograms/ml blood before the treatment, increased up to 125 micrograms/ml blood in 24 h after the treatment and decreased to a near control level in 72 h. Plasma concentration of ornithine carbamoyl-transferase (OCT), another urea cycle enzyme, reached a maximum in 24 h and then decreased a little more rapidly than that of CPS I. On the other hand, alanine aminotransferase activity reached a maximum in 36 h and decreased to a normal level in 96 h. In immunoblot analysis, the native CPS I polypeptide of 160 kD and its fragments of 140 and 125 kD were detected 24-48 h after the treatment. When purified rat CPS I and bovine OCT were injected intravenously into rats, the enzymes disappeared from blood roughly exponentially with apparent half-lives of about 67 and 18 min, respectively. Development of an ELISA for human CPS I and determination of the serum enzyme in various liver diseases remain to be performed.
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PMID:Enzyme-linked immunosorbent assay of carbamoylphosphate synthetase I: plasma enzyme in rat experimental hepatitis and its clearance. 882 9

Hepatoprotective effect of celosian, an acidic polysaccharide isolated from the water extract of the seed of Celosia argentea, was investigated using chemical and immunological liver injury models. Celosian inhibited the elevation of serum enzyme (GPT, GOT, LDH) and bilirubin levels on carbon tetrachloride (CC1(4))-induced liver injuries in rat. In addition, the hepatoprotective effect of celosian was also observed in this model of liver injury by histopathological findings. Moreover, celosian suppressed rises in GPT or mortality on fulminant hepatitis induced by D-galactosamine/lipopolysaccharide (D-Ga1N/LPS) or Propionibacterium acnes/LPS in mice. These findings suggested that celosian is an active component in protection against chemical and immunological hepatitis and the activity was found to be a dose dependent. Celosian showed a concentration dependent inhibitory effect on lipid peroxide (LPO) generation in vitro. Though celosian did not reduce the release of tumor necrosis factor-alpha (TNF-alpha), it protected against recombinant human TNF-alpha (rhTNF-alpha)-induced liver injury in D-galactosamine sensitized mice.
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PMID:Protective effect of celosian, an acidic polysaccharide, on chemically and immunologically induced liver injuries. 886 Sep 60

To study the effect of cyclic AMP on liver dysfunction, dibutyryl cyclic AMP (DBcAMP, 15 mg/kg) was given to rats with acute hepatic failure induced by D-galactosamine (D-Gal; 500 mg/kg) and lipopolysaccharide (i.e., endotoxin) (Et; 0.5 mg/kg). The survival rate was only 7% for rats given D-Gal and Et (control group), while it was 100% for rats given seven doses of DBcAMP, and 53% for rats given two doses. The ALT level was high at 3475 +/- 488 KU in group III, while it was 242 +/- 69 KU in group I, and 376 +/- 49 KU in group II. The hepaplastin test level was decreased at 24 hr in all groups except group I, in which it was high at 55 +/- 11%. The serum tumor necrosis factor (TNF) level was 155 +/- 42 IU/ml in group I, 463 +/- 30 IU/ml in group II, and 1334 +/- 328 IU/ml in group III. The results of the blood biochemistry and liver tissue blood flow studies were better in the DBcAMP-treated groups, and the serum TNF levels were also lower in the treated groups. Histological examination of the liver showed extensive necrosis in the control group, but mild necrosis and inflammatory cell infiltration in the DBcAMP-treated groups. Therefore, treatment with DBcAMP suppressed acute hepatic failure induced by D-Gal and Et, resulting in a significant increase in the survival rate.
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PMID:Protective effects of dibutyryl cyclic AMP on acute hepatic failure in rats. 895 35


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