Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 contribution of cytochrome P450 isozymes CYP2E1 and CYP2B1/2 to chloroform-induced hepatotoxicity taken at 18 hr after the treatment was investigated in rats treated with n-hexane as an inducer of CYP2E1, 2-hexanone as an inducer of CYP2E1 and CYP2B1/2, and phenobarbital (PB) as an inducer of CYP2B1/2. Hepatic damage was evaluated by gross measurement of plasma alanine aminotransferase activity and histopathological examination. All treatments potentiated chloroform-induced hepatic damage. In n-hexane-pretreated rats, the damage was maximal with the middle dose of chloroform (0.2 ml/kg), whereas the damage increased with dose in rats treated with 2-hexanone or PB. The degree of hepatic damage induced with the three pretreatments was in the following order: n-hexane > 2-hexanone = PB with the middle dose of chloroform and PB >> 2-hexanone > n-hexane with the high dose (0.5 ml/kg); little difference among the pretreatments was seen with the low dose (0.1 ml/kg). These findings suggest that CYP2E1 is a low Km isoform and CYP2B1/2 a high Km isoform for chloroform activation. CYP2E1-dependent hepatic damage was characterized by ballooned hepatocytes, which were restricted to the centrilobular area; with CYP2B1/2, more necrotic than ballooned hepatocytes were seen and the necrotic hepatocytes were found not only in the centrilobular but also in the midzonal and periportal areas. Chloroform treatment did not affect the activity of N-nitrosodimethylamine N-demethylase in pretreated rats; the high dose increased the activity in control rats. In contrast, the high dose of chloroform decreased the activity of 7-pentoxyresorufin O-depentylase in all induced rats but not in controls. Immunoinhibition and immunoblot analyses showed that the high dose of chloroform induced CYP2E1 in control rats but decreased CYP2B1/2 in all pretreated rats. These results suggest that although both CYP2E1 and CYP2B1/2 contribute to chloroform-induced hepatic damage, they do so quite differently.
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PMID:Different contributions of cytochrome P450 2E1 and P450 2B1/2 to chloroform hepatotoxicity in rat. 764 16

Investigation by polymerase chain reaction of HBV-DNA in serum from chronic hepatitis B virus carriers is not widely used for routine diagnosis because polymerase chain reaction assays are complex and may be too sensitive. We investigated the sensitivity, the specificity and the possible value for clinical use of a simplified polymerase chain reaction method in which a single, 30 cycles round of polymerase chain reaction is performed using only 10 microliters of serum treated with microwaves. The efficiency of the polymerase chain reaction in amplifying HBV-DNA was greater after microwave irradiation of serum than after alkaline extraction, but lower than after protein digestion and phenol chloroform precipitation. Despite its simplicity and high sensitivity, the assay was very specific. Studies in anti-HBe positive chronic hepatitis B virus carriers demonstrated HBV-DNA sequences in 1/15 (7%) healthy carriers, in 4/20 (20%) patients with slight alanine aminotransferase elevation, in 16/18 (89%) with marked alanine aminotransferase elevation and in all 20 with fluctuating alanine aminotransferase levels. In the latter, HBV-DNA was detected either at exacerbation (two cases), during remission (one case) or both (17 cases). HBV-DNA was detected by classical dot-blot hybridization in only 24/58 (41%) samples that were positive by the simplified polymerase chain reaction method. Although extremely high sensitivity is not achieved, microwave irradiation of serum simplifies considerably the detection of small amounts of HBV-DNA and makes polymerase chain reaction suitable for monitoring patients in whom weak hepatitis B virus replication is associated with ongoing liver disease.
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PMID:Microwave treatment of serum facilitates detection of hepatitis B virus DNA by the polymerase chain reaction. Results of a study in anti-HBe positive chronic hepatitis B. 775 85

Forty halogenated hydrocarbons of known rodent carcinogenicity (24 carcinogens, 16 noncarcinogens), including many promoters of carcinogenesis, nongenotoxic carcinogens, and hepatocarcinogens, were selected for study. The chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. The effects of these 40 chemicals on four biochemical assays [hepatic DNA damage by alkaline elution (DD), hepatic ornithine decarboxylase activity (ODC), serum alanine aminotransferase activity (ALT), and hepatic cytochrome P-450 content (P450)] were determined. Composite predictive parameters are defined as follows: CP = [ODC and P450], CT = [ALT and ODC], and TS = [DD or CP or CT]. The operational characteristics of TS for predicting rodent cancer were sensitivity 58%, specificity 81%, positive predictivity 82%, negative predictivity 57%, and concordance 68%. The concordance for the Ames test (45%) and structural alerts (SA; 46%) was much lower. TS also outperformed the Ames test and SA in producing fewer false positives (the specificity of TS was 81% vs. only 63% for the Ames test and 57% for SA). For predicting the carcinogenicity of the most difficult halogenated hydrocarbons (Ames and SA negative chemicals), TS was capable of successfully predicting the carcinogenicity of 8 (carbon tetrachloride, chloroform, alpha-hexachlorocyclohexane, kepone, mirex, monuron, p,p'-DDE, and 2,4,6-trichlorophenol) out of 16 of these non-DNA-reactive halogenated hydrocarbon carcinogens. All 8 of these halogenated hydrocarbons were positive in either CP or CT. This evidence shows that nongenotoxic carcinogenesis is best predicted by nongenotoxic parameters such as CP or CT (components of the predictor TS).
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PMID:Predicting rodent carcinogenicity of halogenated hydrocarbons by in vivo biochemical parameters. 790 85

Previous studies have indicated that adrenergic agents may potentiate the hepatotoxicity of compounds such as CCl4. Methamphetamine is a powerful central nervous system stimulating drug which also possesses significant adrenergic activity, and its effects on CCl4 hepatotoxicity were examined in male ICR mice. Cotreatment of mice with methamphetamine (15 mg/kg i.p.) resulted in a significant increase in the hepatocellular necrosis produced by minimally toxic to moderately toxic doses of CCl4 (0.005-0.02 ml/kg i.p.), as indicated by changes in serum alanine aminotransferase activity and by histopathologic examination. Methamphetamine alone at this dosage was not hepatotoxic. The ability of methamphetamine to potentiate CCl4 hepatotoxicity was dose-related and became statistically significant at methamphetamine doses of 10 mg/kg or greater. Pretreatment of animals with either the selective alpha-1 adrenoreceptor antagonist prazosin (5 mg/kg i.p.) or the selective alpha-2 adrenoreceptor antagonist yohimbine (5 mg/kg i.p.) blocked the methamphetamine potentiation. The increase in CCl4 toxicity produced by methamphetamine was not associated with an increase in hepatic concentrations of either CCl4 or one of its major metabolites, chloroform. The increase in toxicity was associated, however, with increases in the in vivo covalent binding of radiolabeled CCl4 to both hepatic proteins and lipids. The cause of the increased covalent binding was not identified, but did not appear to be related to methamphetamine-induced hepatic glutathione suppression. The results of this study suggest that methamphetamine potentiates CCl4 through an adrenoreceptor-related mechanism that may involve either the increased production or diminished conjugation of the reactive metabolites normally formed during the metabolism of CCl4.
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PMID:Methamphetamine potentiation of carbon tetrachloride hepatotoxicity in mice. 796 67

Chloroform (CHCl3) is widely used in the manufacture of drugs, cosmetics, plastics and cleaning agents. It is also found in chlorinated drinking water. This study was designed to investigate the toxic effect of CHCl3 on isolated male rat hepatocytes using several toxicity parameters. The hepatocytes were isolated by a collagenase perfusion technique and the cell viability was determined by Trypan blue exclusion. The leakage of cytosolic enzymes such as aspartate transaminase (AST) and alanine transaminase (ALT) after treatment with CHCl3 was measured. Reduced glutathione content (GSH) and its related enzymes, glutathione reductase (GSH-Rx) and glutathione peroxidase (GSH-Px), were also evaluated to study the effect of CHCl3 on hepatocytes. Exposure to 100 and 1000 ppm CHCl3 results in a significant decrease in cell after 30 min incubation. However, the effect of 1 and 10 ppm concentrations was observed at 60 min incubation. AST leakage was significantly increased in all treatment groups, while ALT was significantly increased at 100 and 1000 ppm CHCl3 after 60 and 30 min, respectively. As early as 15 min, GSH was decreased significantly at 1000 ppm, but at 100 and 10 ppm CHCl3 the decrease in GSH began after 30 and 120 min, respectively. GSH-Px activity did not changed. However, the activity of GSH-Rx was significantly decreased at 1000 ppm CHCl3 and at the same time GSH content was decreased. The data indicate that the toxic effect of CHCl3 was dose- and time-dependent. The degree of GSH depletion correlated with increased cytotoxicity and decreased GSH-Rx activity due to CHCl3.
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PMID:The mechanism of chloroform toxicity in isolated rat hepatocytes. 835 69

Dimethyl sulfoxide (DMSO) can protect the liver from injury produced by a variety of hepatotoxicants when administered prior to or concomitant with the toxicants. This protective action has previously been attributed to DMSO-induced inhibition of bioactivation of the compounds to toxic intermediates. In these studies, the ability of DMSO to provide protection when administered 10 hr after a toxicant was evaluated in several animal models of xenobiotic-induced liver and kidney injury. In the guinea pig model of halothane-associated hepatotoxicity, male outbred Hartley guinea pigs received 2 ml/kg DMSO 10 hr after an inhalation exposure to 1.0% halothane, 40% O2 for 4 hr. DMSO decreased the extent of liver necrosis as indicated by a threefold decrease in plasma alanine aminotransferase activity 48 hr after exposure and a reduction in the incidence and extent of zone 3 necrosis. These results do not appear to be due to alterations in halothane biotransformation since DMSO administered at 10 hr after halothane had no affect on plasma concentrations of the halothane metabolite tritluoroacetic acid or covalent binding by reactive halothane biotransformation intermediates to hepatic protein. In addition, administration of the structurally analogous biotransformation inhibitor diallyl sulfide at 10 hr after halothane also had no affect on biotransformation or covalent binding but provided no protection from liver injury. Hepatic glutathione concentrations in the guinea pigs 24 hr after halothane exposure were also unaffected by late treatment with DMSO. Further studies in male Sprague-Dawley rats demonstrated the ability of DMSO to decrease the hepatic injury resulting from oral administration of 1.0 ml/kg chloroform or 0.5 ml/kg bromobenzene when administered 10 hr after either toxicant. The chloroform-treated rats also developed renal tubular necrosis with large increases in plasma creatinine and urea nitrogen, which were completely ameliorated by DMSO. Elucidating the mechanism(s) of this protective action of late DMSO administration should provide insight into the cascade of events that lead to liver and kidney injury from toxicants and, hopefully, therapeutic modalities for individuals suffering from acute, progressing, xenobiotic-induced hepatitis.
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PMID:Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney. 900 50

There are conflicting results in the literature concerning the effect of gavage vehicle, corn oil (CO) versus aqueous suspension, on the toxicity of haloalkanes. The purpose of our study was to assess the influence of oral dosing vehicle on the acute hepatotoxicity of CCl4 and nephrotoxicity of CHCl3. Male Sprague-Dawley rats, fed ad libitum, were treated (po) with single doses of CCl4 or CHCl3 using corn oil (CO), or an aqueous preparation (5%) of Emulphor (EL620) or Tween-85 (Tw-85) as vehicle (10 ml/kg). Rats were killed 48 h after treatment. Blood was collected for plasma alanine aminotransferase (ALT) determination and renal cortical slices were prepared for p-aminohippuric acid (PAH) incorporation. The comparison, between gavage vehicles, of the slopes and ED50 of the dose-response curves, although not significantly different, indicated clear trends for enhanced potency with CO for CHCl3 nephrotoxicity but not for CCl4 hepatotoxicity. However, ALT values, a measure of the severity of effect for CCl4, also indicated that CO, when compared to EL620 and Tw-85, tended to enhance CCl4 hepatotoxicity at low toxicity incidence. Furthermore, CO clearly enhanced the severity of effect for CHCl3 nephrotoxicity, as measured by the slice-to-medium PAH ratios, at high dosage. The greater severity of the lesion produced by exposure to these chemicals, when administered in CO, is consistent with the trends observed for their potency (dose-response curves). Our results agree with an increased toxicity of haloalkanes by the gavage vehicle CO reported in the literature. Thus, CO should be considered a potential confounder in hepato- and nephrotoxicity assays.
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PMID:Effect of dosing vehicle on the hepatotoxicity of CCl4 and nephrotoxicity of CHCl3 in rats. 923 80

The relationship was investigated between biochemical and morphological changes in chloroform (CHCl3)- and carbon tetrachloride (CCl4)-induced liver damage. The time courses of hepatic microsomal cytochrome P450 (CYP) content, hepatic microsomal CYP2E1 activity, hepatic reduced glutathione (GSH) content, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were examined in relation to the liver morphology in rats orally treated with CHCl3 or CCl4 (3.35 mmol/kg). The CYP content and the activity of CYP2E1 markedly decreased in the CCl4-treated rats 3 h after treatment compared to much lower decreases in the CHCl3-treated rats. The hepatic GSH content was decreased to a similar extent in both groups of rats at 3 h after treatment; in the CCl4-treated rats, the GSH content continued to decrease, reaching a minimum at 24 h and without attaining the normal level at 72 h after treatment. By contrast, hepatic GSH content in the CHCl3-treated rats began to increase from 6 h, attaining complete recovery 48 h after treatment. Plasma ALT and AST activities were significantly elevated by CCl4 as early as 3 h after treatment, while the activities in the CHCl3-treated rats did not increase until 6 h after treatment. In both groups of rats, ALT and AST activities reached a maximum at 24 h, and gradually decreased, remaining at abnormal levels at 72 h. Hepatic cells in the CCl4-treated rats were found to be necrotic as early as 3 h post-treatment, whereas few or no morphological changes appeared in the liver of CHCl3-treated rats. The extent of necrosis was at a maximum 24 h after treatment in both CHCl3- and CCl4-treated rats. In addition, some necrotic cells remained in the liver of CCl4-treated rats 72 h after treatment, while the necrosis in the CHCl3-treated rats was almost negligible. The present results indicate that almost the same time-courses of biochemical and morphological changes were followed in rats of both the CHCl3- and CCl4-treated groups.
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PMID:Time courses of hepatic injuries induced by chloroform and by carbon tetrachloride: comparison of biochemical and histopathological changes. 933 1

Effects of single intraperitoneal (i.p.) administration of carbon tetrachloride (CCl4), chloroform (CHCl3), and dichloromethane (CH2Cl2) on lipoproteins in plasma and liver were investigated in rats. Changes in lipoproteins caused by these solvents were compared with changes in traditional hepatotoxicity markers such as GPT (ALT). Following the administration, concentrations of lipoproteins (VLDL, LDL, HDL), triglyceride, cholesterol, and GPT activity in plasma were determined through changes in liver weight, liver content of triglyceride, malon dialdehyde (MDA), and glutathione (GSH). Time-course study revealed that changes in plasma and liver reached their peaks at 19 or 32 hr following the administration of CCl4 or CHCl3. Peaks of changes were observed at 8 or 19 hr following the administration of CH2Cl2. Dose dependency of these changes was investigated at dosages of 3, 30, and 300 mg/kg of CCl4 or CHCl3, and 300, and 1,000 mg/kg of CH2Cl2. Significant decreases in triglyceride and apolipoproteins in VLDL fraction were observed at 3 mg/kg of CCl4. Such VLDL components decreased at 30 mg/kg of CHCl3. HDL decreased significantly at 300 mg/kg of CH2Cl2 and marked increase in LDL occurred at 1,000 mg/kg of the solvent. Liver weight and liver content of triglyceride and MDA significantly increased at 30 mg/kg of CCl4, while significant increase in GPT activity was observed at 300 mg/kg of CCl4 and CHCl3. GPT increased significantly at 1,000 mg/kg of CH2Cl2. These results revealed that changes in plasma lipoproteins can serve as sensitive and simple markers for liver disorders caused by chlorinated hydrocarbon solvents such as CCl4, CHCl3, or CH2Cl2.
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PMID:Changes in plasma lipoproteins as toxicity markers for carbon tetrachloride, chloroform, and dichloromethane. 934 25

Dichloroacetic acid (DCA) and chloroform (CHCl3) are both major by-products of drinking water chlorination and DCA increases the hepatotoxicity of CHCl3. In this study, we further characterized this effect and investigated DCA-induced alterations of CHCl3 disposition and metabolism as a possible mechanism for this interaction. Both adult male and female Sprague-Dawley rats were gavaged with three doses (09:00, 16:00 and 09:00 the next morning) of DCA (each 2.45 mmol/kg), then challenged with an i.p. injection of CHCl3 (3.12 or 9.35 mmol/kg). Hepatic damage was assessed 24 h after CHCl3 administration as increased alanine aminotransferase (ALT), ornithine carbomyl transferase (OCT) and bilirubin in plasma. In a separate experiment, rats were pretreated with DCA or were given 14CHCl3 at the same dosages. The disposition of 14C in various tissues and covalent binding of 14CHCl3-derivatives to liver proteins and lipids were determined 1 h later. CHCl3-induced hepatotoxicity was significantly more severe in DCA-pretreated groups. ALT and OCT were more markedly elevated in DCA + CHCl3 (3.12 mmol/kg) groups than NaCl +CHCl3 animals. Plasma bilirubin content was elevated only in DCA + CHCl3 groups and females were more susceptible to this effect. The responses of rats to DCA treatment were somewhat gender-different. DCA treatment increased total cytochrome P450 in females, but not in males. Hepatic glutathione concentration was elevated in males after DCA treatment, but not in females. In the present study we confirmed that DCA pretreatment potentiates the CHCl3-hepatotoxicity of both male and female rats. However, there was little evidence that DCA pretreatment significantly affected CHCl3 disposition or increased CHCl3 binding in vivo.
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PMID:Dichloroacetic acid pretreatment of male and female rats increases chloroform-induced hepatotoxicity. 939 56


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