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)

Previous work has established the marked potentiation of CCl4 hepatoxicity by prior exposure to chlordecone (CD). This study was conducted to determine if prior exposure to CD results in enhancement of CCl4-induced destruction of the hepatic microsomal mixed-function oxygenase (MFO) system. Male Sprague-Dawley rats received a single oral dose of CD (10 mg/kg) or corn oil vehicle alone (1 ml/kg) 24 hr prior to a single ip injection of CCl4 (0-100 microliter/kg). Mirex (M; 10 mg/kg) and phenobarbital (PB; 80 mg/kg/day for two days) were used as negative and positive controls respectively for the potentiation of CCl4 hepatotoxicity. Hepatotoxicity was evaluated 24 hrs after CCl4 administration by elevations of three serum enzymes (GPT, GOT, and ICD). The key hepatic microsomal MFO parameters measured were microsomal protein, cytochrome P-450 content, glucose-6-phosphatase (G-6-Pase), and aminopyrine demethylase (APD). As previously demonstrated using a subchronic dietary pretreatment protocol, CD potentiated CCl4 hepatotoxicity over a range of CCl4 doses to a greater extent than PB or M, as judged by elevations in serum enzymes. PB caused the greatest increase in total P-450 content and the greatest increase in CCl4-mediated destruction of microsomal protein and APD activity. M caused the least destruction of total hepatic cytochrome P-450, despite the same level of cytochrome P-450 as in the PB group. CD treatment caused the greatest decrease in G-6-Pase activity in comparison to PB or M pretreatments and a similar degree of P-450 destruction as observed with the PB group. These findings suggest that in general, CCl4-induced destruction of hepatic MFO parameters measured in this study is disproportional to the known degree of potentiated hepatotoxicity by the pretreatments and does not accurately reflect the potentiation of CCl4 hepatotoxicity by CD.
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PMID:Destruction of hepatic mixed-function oxygenase parameters by CCl4 in rats following acute treatment with chlordecone, Mirex, and phenobarbital. 619 92

The propensity of chlordecone (CD) to potentiate CCl4 hepatotoxicity in rats of either sex has been well documented. The objective of the present study was to investigate the hepatotoxic effects of CD-CCl4 interaction in adrenalectomized rats. Adrenalectomized rats were maintained on 0 or 10 ppm CD and on day 15 they received a single ip injection of 25 microL CCl4/kg. Hepatotoxicity was assessed by hepatofunctional, biochemical and histopathological parameters, 24 hrs after CCl4 challenge. CCl4-induced hepatobiliary dysfunction and elevation of serum enzymes (GPT, GOT, ICD and OCT) were evident. Hepatic dysfunction was most severe in adrenalectomized rats receiving CD-CCl4 combination treatment. Histopathology of liver exhibited extensive fatty infiltration in the entire lobular structure accompanied by some necrosis. These data indicate that the capacity of CD to potentiate CCl4 hepatotoxicity is unaffected in adrenalectomized rats.
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PMID:Effect of adrenalectomy on chlordecone potentiation of carbontetrachloride hepatotoxicity. 619 34

Hepatotoxicity of vinylidene chloride (1, 1-dichloroethylene, VDC) in rats was evidenced by increases of serum enzyme activities of the aminotransferases (GOT, GPT) and sorbitol dehydrogenase (SDH). Simultaneous treatment with ethanol (4.8 g kg-1; p.o.) totally inhibited these hepatotoxic effects, whereas pretreatment with the same ethanol dose 24 h prior to VDC had no effect. Dithiocarb or (+)-catechin (0.2 g kg-1; p.o.), administered simultaneously with VDC, significantly reduced the VDC-induced increments of serum enzyme activities. Pretreatment with 5% ethanol for 7 days instead of drinking water increased the hepatotoxicity of a single dose of VDC. The combined treatment with VDC (0.125-0.2 g kg-1, twice weekly) and 5% ethanol for 4 weeks led to only small increases of serum enzyme activities as compared with controls treated with VDC alone. However, 60% lethality occurred in the VDC-ethanol group. Administration of either dithiocarb or (+)-catechin with VDC totally antagonized the observed lethality. Metabolic studies with VDC in a closed exposure system indicated that simultaneous treatment with ethanol or dithiocarb totally depressed the metabolic removal of VDC, whereas (+)-catechin had no effect.
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PMID:Influence of alcohol, dithiocarb and (+)-catechin on the hepatotoxicity and metabolism of vinylidene chloride in rats. 630 45

Hepatotoxicity of bromobenzene (2 mmole/kg) in combination with toluene or chlorobenzene (4 mmole/kg each) were studied in vivo on the basis of GPT elevation and histological examinations. Both toluene and chlorobenzene suppressed bromobenzene hepatotoxicity 24 hr after the treatment, and chlorobenzene dramatically potentiated the toxicity at 48 hr. The glutathione level became lower at 12 hr and recovered at 24 hr when bromobenzene was given alone. The recovery delayed until 48 hr when chlorobenzene was coadministered. In experiments in vitro with microsomes from phenobarbital-pretreated rats, both toluene and chlorobenzene at 0.6 mM inhibited p-bromophenol formation noncompetitively but had no effect on o-isomer formation. Multiple factors may determine overall hepatotoxicity in combined exposure; bromobenzene hepatotoxicity will be suppressed in the early phase owing to metabolic inhibition of 3,4-epoxidation, but potentiated later because of delayed recovery in the glutathione level. A time-saving yet reliable assay system with an ECD-gas chromatograph was developed for bromobenzene metabolism study.
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PMID:Mechanisms for modification of bromobenzene hepatotoxicity by coadministered toluene and chlorobenzene. 647 68

Hepatotoxicity of aflatoxin B1 (2.0 and 4.0 mg/kg i.p.) as determined by plasma enzyme activities (GPT and GOT), liver triglycerides and histopathologic changes was enhanced in rats pretreated with four oral doses of ethanol (4.0 g/kg each) at 48, 45, 24 and 21 hrs prior to aflatoxin B1 administration. Pretreatment with ethanol (4.0 g/kg) slightly increased liver weight without changing hepatic microsomal protein contents. Also it caused an increase in microsomal aniline hydroxylase but a decrease in p-nitroanisole-o-demethylase, 48 hrs after the first ethanol dose. In the rats pretreated with ethanol, aflatoxin B1 was metabolized at a higher extent to aflatoxins M1 and Q1. These results suggest that an increased hepatotoxicity of aflatoxin B1 after pretreatment with ethanol may presumably due to an increase in microsomal formation of active aflatoxin B1 metabolite.
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PMID:Enhanced hepatotoxicity of aflatoxin B1 by pretreatment of rats with ethanol. 681 83

Prior consumption of a diet containing the food antioxidant, butylated hydroxyanisole (BHA), by female mice prevented the development of or minimized the acute liver damage caused by monocrotaline, acetaminophen, or bromobenzene. In contrast, neither the incidence nor the severity of carbon tetrachloride-induced hepatotoxicity was affected by dietary BHA. Hepatotoxicity was judged by plasma alanine aminotransferase and aspartate aminotransferase levels, hepatic cytochrome P-450 content, and liver histology. The protective effect of BHA against acetaminophen-induced hepatotoxicity was not demonstrated in male mice. The observed protection by dietary BHA against acetaminophen- and bromobenzene-induced hepatotoxicity was associated with the increase of liver glutathione. It is concluded that the protective action of BHA is dependent upon the nature of the toxic agent.
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PMID:Protective role of dietary butylated hydroxyanisole against chemical-induced acute liver damage in mice. 685 90

The influence of Zn on the acute hepatotoxicity of pyrrolizidine alkaloids (PAs) was determined in male rats. Zinc, 72 mumol/kg as ZnCl2, was administered ip for 3 consecutive days, followed 16 h after the last dose by a single ip injection of purified mixed PAs (80, 120, or 160 mg/kg) obtained from tansy ragwort (Senecio jacobaea). Hepatotoxicity of the PAs was assessed by measuring the activities of plasma glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) and by histological examination of the liver. There was a dose-dependent increase in plasma GOT and GTP 24 h after PA administration, whereas no significant increase of these enzymes was seen after administering Zn alone. The 7-fold increase in plasma GOT and 12-fold increase in GPT after PA (120 mg/kg) were reduced to 2.4- and 2.1-fold, respectively, by Zn pretreatment. The PA-induced liver necrosis was either reduced in severity or abolished by Zn when the PA dose was 80 or 120 mg/kg. These results suggest a protective effect of Zn against PA hepatotoxicity. The protective effect was associated with a marked increase in liver metallothionein and a significant decrease in hepatic cytochrome P-450 content, aminopyrine N-demethylase activity, and in vitro microsomal conversion of the PAs to pyrroles. Liver nonprotein sulfhydryls were unchanged. The possible role of metallothionein in the sequestration of pyrrole metabolites merits further investigation.
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PMID:Protective action of zinc against pyrrolizidine alkaloid-induced hepatotoxicity in rats. 709 90

Increases in the use of methanol (MeOH) as a transportation fuel would result in greater potential for inhalation exposure. Because oral exposure to MeOH potentiates the hepatotoxicity of carbon tetrachloride (CCl4), we examined the ability of inhaled MeOH to potentiate CCl4 hepatotoxicity and the time course of injury and recovery. Adult male F-344 rats were exposed to 0 or to 10,000 ppm MeOH by inhalation for 6 h and gavaged with 0.075 ml CCl4/kg 24 h later. Hepatotoxicity was assessed 0.5, 1, 1.5, 2, 3, 7, 15, 30, and 61 d after CCl4 exposure. For CCl4 alone, hepatotoxicity was most severe at 0.5 and 1 d, when minimal centrilobular hepatocellular necrosis and predominately mild centrilobular hepatocellular vacuolar degeneration occurred. By d 3, the livers from the CCl4 rats were histologically normal. For MeOH+CCl4, peak severity of hepatic injury was at 1 and 1.5 d, when moderate centrilobular necrosis and moderate/marked centrilobular degeneration occurred. MeOH+CCl4 resulted in serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that were increased, relative to CCl4 alone, 171- and 113-fold, respectively, on d 1, and 166- and 140-fold, respectively, on d 1.5. Significant serum elevations in MeOH+CCl4 rats, relative to CCl4 alone rats, were present until d 7 and d 15 for AST and ALT, respectively. By d 3 and d 7, degeneration and necrosis, respectively, due to MeOH+CCl4 were essentially resolved. On d 7, the MeOH+CCl4 hepatic injury consisted mainly of chronic inflammation and centrilobular fibrosis. By d 30, the livers of MeOH+CCl4 rats were histologically normal. These data demonstrate that inhaled MeOH potentiates the hepatotoxicity of orally ingested CCl4, increasing the severity of CCl4 hepatotoxicity as well as the time required for recovery.
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PMID:Potentiation of carbon tetrachloride hepatotoxicity by inhaled methanol: time course of injury and recovery. 756 18

1. Hepatotoxicity is the most common finding in patients with iron overload since the liver is the major recipient of iron excess, even though the kidney could be a target of iron toxicity. The effect of iron overload was studied in the early stages after iron-dextran injection in rats, as a model for secondary hemocromatosis. 2. Total hepatic and kidney iron content was markedly elevated over control values 20 h after the iron administration. Plasma GOT, GPT and LDH activities were not affected, suggesting that liver cell permeability was not affected by necrosis. 3. Spontaneous liver chemiluminescence was measured as an indicator of oxidative stress and lipid peroxidation. Light emission was increased four-fold 6 h after iron supplementation. 4. Increases in the generation of thiobarbituric acid reactive substances (TBARS in liver and kidney homogenates were detected after iron administration. 5. The activities of catalase, SOD and glutathione peroxidase were determined. Enzymatic activities declined in liver homogenates by 25, 36 and 32%, respectively, 20 h after iron injection. These activities were not affected in kidney as compared to control values, except for SOD activity that was decreased by 26%. 6. The content of alpha-tocopherol was decreased by 31% in whole kidney homogenates and by 40% in plasma. 7. Our data indicate that lipid peroxidation occurs after mild iron overload both in liver and kidney. Enzymatic antioxidants are consumed significantly in liver and alpha-tocopherol content decreases in kidney, suggesting an organ-specific antioxidant effect.
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PMID:Effect of mild iron overload on liver and kidney lipid peroxidation. 764 Jun 23

The hepatotoxicity of the herbal plant germander and that of one of its major furanoneoclerodane diterpenes, teucrin A, were investigated in mice. Teucrin A was found to cause the same midzonal hepatic necrosis as observed with extracts of the powedered plant material. Evidence that bioactivation of teucrin A by cytochromes P450 (P450) to a reactive metabolite(s) is required for initiation of the hepatocellular damage is provided by results of experiments on the induction and inhibition of P450 and from studies on the effects of glutathione depletion. Pretreatment of mice with the P450 inducer phenobarbital enhanced the hepatotoxic response, as indicated by an increase in plasma alanine aminotransferase (ALT) levels and hepatic necrosis, while pretreatment with the P450 inhibitor piperonyl butoxide markedly attenuated the toxic response. Hepatotoxicity of teucrin A also was increased following pretreatment with the inhibitor of glutathione synthesis buthionine sulfoximine. Most importantly, the tetrahydrofuran analog of teucrin A, obtained by selective chemical reduction of the furan ring, was not hepatotoxic, a result that provides strong evidence that oxidation of the furan ring moiety of the neoclerodane diterpenes is involved in the initiation of hepatocellular injury caused by germander.
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PMID:Hepatotoxicity of germander (Teucrium chamaedrys L.) and one of its constituent neoclerodane diterpenes teucrin A in the mouse. 769 42


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