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)

Chloroform (TCM), a water disinfection by-product, induced liver tumors in female mice when administered by gavage in corn oil but not when given in drinking water at comparable daily doses. Because short-term studies showed that the gavage doses also induced liver toxicity, it has been suggested that the liver tumor response occurs secondary to cytotoxicity and consequent regenerative hyperplasia induced by oxidative metabolism of TCM to the toxic dihalocarbonyl intermediate. This study compares dose-response relationships of gavage-administered chlorinated/brominated trihalomethanes for hepatotoxicity, replicative DNA synthesis, and hepatocarcinogenicity in female B6C3F1 mice. The liver tumor data were obtained from previously published studies. Because bromine is a better leaving group than chlorine, metabolism of bromodichloromethane (BDCM) should produce the same intermediates as would be formed from TCM. Hence, the toxicity and carcinogenicity of BDCM was expected to be qualitatively similar to that of TCM. Dose responses for liver weight, serum sorbitol dehydrogenase and alanine aminotransferase (ALT) activities, hepatocyte degeneration, and hepatocyte labeling index (LI, a measure of replicative DNA synthesis) in female mice were similar following 3 weeks of gavage administration (once per day, 5 days per week) with TCM, BDCM, or chlorodibromomethane (CDBM). Fits of composite data for these trihalomethanes to a Hill equation model revealed sigmoidal dose responses for ALT activity and hepatocyte LI and a nearly linear low-dose response for liver tumor incidence. For this family of chemicals, the mouse liver tumor response was not associated with an elevated hepatocyte LI at doses of approximately 1 mmol/kg or less. High incidences of liver tumors were observed with BDCM and CDBM at doses that had a marginal effect or no effect on the hepatocyte LI. Thus, the carcinogenic effects of trihalomethanes are not simply a consequence of cytotoxicity and regenerative hyperplasia. The possible contributions from other activation pathways, including GSH conjugation and reductive metabolism, need to be considered in assessments of the carcinogenicity of the trihalomethanes.
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PMID:Regenerative hyperplasia is not required for liver tumor induction in female B6C3F1 mice exposed to trihalomethanes. 987 7

Effects of a single dose of betaine on the chloroform-induced hepatotoxicity were examined in adult male ICR mice. Administration of betaine (1000 mg/kg, ip) 1 to 7 hr prior to a chloroform challenge (0.25 ml/kg, ip) resulted in remarkable enhancement of hepatotoxicity as indicated by increases in serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. The potentiation of hepatotoxicity was most significant when mice were treated with betaine 4 hr earlier than chloroform. However, a 24 hr prior administration of betaine protected the animals from induction of the chloroform hepatotoxicity. Thus, its effect appeared to be highly dependent on the time lapse from the betaine pretreatment to the challenge of mice with chloroform. Betaine treated either 4 or 24 hr prior to sacrifice did not alter the hepatic contents of cytochrome P-450, cytochrome b5, or NADPH cytochrome P-450 reductase activity. Accordingly the hepatic microsomal p-nitroanisole O-demethylase, aminopyrine N-demethylase, or p-nitrophenol hydroxylase activities were not influenced by the betaine pretreatment. Betaine was shown not to affect any of the enzyme activities associated with glutathione (GSH) conjugation reaction, such as glutathione S-transferases (GSTs), glutathione disulfide (GSSG) reductase and GSH peroxidase irrespective of the time of its administration. When betaine was administered to mice 2-6 hr prior to sacrifice, hepatic GSH level, but not plasma GSH, was decreased significantly. Enhancement of the chloroform hepatotoxicity by betaine correlated well with the reduction in hepatic GSH levels. Both hepatic and plasma GSH levels were elevated in mice 24 hr following the betaine treatment. The results suggest that betaine affects induction of the chloroform hepatotoxicity by modulating the availability of hepatic GSH, which appears to be associated with its role in the transsulfuration pathway in the liver.
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PMID:Effects of singly administered betaine on hepatotoxicity of chloroform in mice. 973 16

The discovery of a V-type ATPase in the gram-negative bacterium Thermus thermophilus HB8 (YOKOYAMA et al., J. Biol. Chem. 265, 21946, 1990) was unexpected, since only eukaryotic endomembranes and archaea were thought to contain this enzyme complex, and horizontal gene transfer was suggested to explain the finding. We examined membrane-associated ATPases from representatives of several groups of the genus Thermus. The enzymes were extracted with chloroform and purified by ion exchange chromatography or native gel electrophoresis. One novel Islandic isolate, T. scotoductus SE-1, as well as strain T. filiformis from New Zealand, possessed F-ATPases, as judged by the typical five subunit composition of the F1-moiety, sensitivity to azide, insensitivity to nitrate and a strong crossreaction with antibodies against the F1-ATPase from E. coli. In addition, N-terminal amino acid sequencing of the beta subunit from T. scotoductus SE-1 confirmed its homology with beta subunits from known F-ATPases. In contrast, the same extraction procedure released a V-ATPase from the membranes of T. thermophilus HB27 and T. aquaticus YT-1. The related species Meiothermus (formerly Thermus) chliarophilus ALT-8 also possessed a V-ATPase. All V-ATPases examined in this study contained larger major subunits than F-ATPases, crossreacted with antiserum against subunit A of the V-ATPase from the archaeon Halobacterium saccharovorum, and the N-terminal sequences of their major subunits were homologous to those of other V-ATPases. Sequences of the 16S rRNA gene clearly placed T. scotoductus SE-1, along with other non-pigmented Thermus strains, as a distinct species close to T. aquaticus. Our results suggested that at least two members of the genus, T. scotoductus SE-1 and T. filiformis, contain an F-ATPase, whereas several others possess a V-ATPase. These data could indicate a greater diversity of the genus Thermus than was previously thought. Alternatively, the genus may consist of species where horizontal gene transfer has occurred and others, where it has not.
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PMID:F-and V-ATPases in the genus Thermus and related species. 974 Nov 6

Chloroform (CHCl3) and bromodichloromethane (BDCM) are generally the two most prevalent disinfection by-products formed during chlorination of drinking water, and both have been shown to be hepatotoxic, nephrotoxic, and carcinogenic in rodents. As the toxicity of these trihalomethanes (THMs) has most often been studied with corn oil as the vehicle of administration, the objectives of this study were to assess hepatotoxicity after exposure to single, low dosages of CHCl3 and BDCM given orally in an aqueous vehicle to estimate a lowest-observed-adverse-effect level (LOAEL) and a no-observed-adverse-effect level (NOAEL) and to compare toxic potency. Ninety-day-old male Fischer 344 rats were gavaged with either 0.125, 0.1875, 0.25, 0.5, 0.75, 1.0, or 1.5 mmol CHCl3 or BDCM/kg body weight in 10% Alkamuls EL-620 (5 ml/kg body weight). At 24 h postgavage, serum was collected for analysis of clinical chemistry indicators of liver damage. Both CHCl3 and BDCM induced dose-dependent hepatotoxicity; serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase were elevated significantly over control at 1.5, 1.0, and 0.5 mmol/kg. At these dose levels after 24 h, the two THMs appeared to be equipotent hepatotoxicants. Additional assessments at later time points demonstrated that BDCM causes more persistent liver damage than CHCl3 (Lilly et al., 1997). At 0.25, 0. 1875, and 0. 125 mmol of either THM/kg, significant increases over control were not detected for any measured endpoint. Therefore, these data indicate that the acute, oral NOAELs and LOAELs for liver toxicity are 0.25 and 0.5 mmol/kg, respectively, for both CHCl3 and BDCM. These determinations should provide a basis to establish new exposure limits for One-Day Health Advisories for these prevalent THMs.
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PMID:NOAEL and LOAEL determinations of acute hepatotoxicity for chloroform and bromodichloromethane delivered in an aqueous vehicle to F344 rats. 974 4

These studies were designed to investigate the dose response for liver injury and tissue repair induced by exposure to four structurally and mechanistically dissimilar hepatotoxicants, individually and as mixtures. The objective was to illuminate the impact of the extent and timeliness of tissue repair on the ultimate outcome of toxicity. Dose-response relationships for trichloroethylene (TCE), allyl alcohol (AA), thioacetamide (TA), and chloroform alone or as mixtures were studied. Male Sprague-Dawley rats (200-250 g) received a single intraperitoneal injection of individual toxicants as well as mixtures of these toxicants. Liver injury was monitored by plasma enzyme (ALT and SDH) levels and histopathology. Tissue regeneration was measured by [3H]thymidine incorporation into hepatic nuclear DNA. Individually, TCE, TA, and AA administration, over a 10- to 12-fold dose range, revealed a dose-related increase in injury as well as tissue repair up to a threshold dose. Beyond this threshold, tissue repair was delayed and attenuated, and liver injury progressed. Mixtures of the four chemicals at the higher doses used in individual dose-response studies resulted in 100% mortality. Hence, mixtures at the lower two doses were selected for further study. Additional lower doses were also included to better understand the dose-response relationship of mixtures. Results of these studies support the observations of individual chemicals. Higher and sustained repair was observed at low dose levels. These studies show that the extent of injury at early time points correlates well with the maximal stimulation of the opposing response of tissue repair. It appears that the toxicity of the mixture employed in these studies is roughly additive and correlates well with tissue repair response. These initial studies suggest that a biologically based mathematical model can be constructed and tested to extrapolate the outcome of toxicity from a given dose of individual compounds as well as their mixtures, where the responses measured are injury on the one hand and compensatory tissue repair on the other.
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PMID:Toxicant-inflicted injury and stimulated tissue repair are opposing toxicodynamic forces in predictive toxicology. 1034 Nov 47

Dimethyl sulfoxide (DMSO) has previously been reported to protect against hepatotoxicity resulting from chloroform (CHCl3) or bromobenzene (BB) when given 10 hr after the toxicant. The object of these studies was to further demonstrate the latent protective ability of DMSO by administering it at a much later time (24 hr) following toxicant exposure. In addition, a more detailed evaluation of the lesions was performed to better characterize the lesion progression and resolution. Male Sprague-Dawley rats received a hepatotoxic oral dose of either CHCl3 (1.0 ml/kg) or BB (0.5 ml/kg) and then received 2 ml/kg DMSO intraperitoneally 24 hr later. With both toxicants, limited centrilobular lesions were already present by the time DMSO was administered. Without treatment, liver injury rapidly progressed so that by 48 hr it occupied 40-50% of the liver, with accompanying large increases in plasma alanine aminotransferase (ALT) activity. Administration of DMSO greatly attenuated lesion development for both toxicants; the area injured was reduced by more than 4-fold, accompanied by a decrease in 48 hr ALT activity of 8-16-fold. The ability of DMSO to intervene in the development of liver injury at such a late time appears to be unique and may provide insight into therapies for acute xenobiotic-induced hepatitis.
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PMID:Hepatoprotection by dimethyl sulfoxide. I. Protection when given twenty-four hours after chloroform or bromobenzene. 1035 11

Acute toxic hepatic necrosis is common and may be fatal. Predicting clinical outcome may be aided by following serum markers that could indicate recovery or may signify massive (substantial) destruction of functional liver mass. Previously, in a published case of chloroform poisoning, we serially assayed serum biomarkers of hepatocellular necrosis (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase) and markers of hepatocellular regeneration (alpha-fetoprotein, retinol-binding protein, gamma-glutamyl transferase, and des-gamma-carboxyprothrombin). We noted a decline in necrotic markers and a synchronous elevation in regenerative markers, which could be suggestive of a favorable outcome in similar cases. We now report 6 Amanita mushroom poisonings with favorable outcome and 2 fatal acetaminophen poisonings in which the same markers were observed. Our results further support our hypothesis that a sustained decline in serum markers of hepatocyte necrosis with a concurrent elevation in regenerative markers could aid in prediction of favorable outcome in patients with acute liver injury.
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PMID:Biomarkers of liver regeneration allow early prediction of hepatic recovery after acute necrosis. 1047 40

Dimethyl sulfoxide (DMSO) has previously been shown to attenuate chloroform (CHCl3) and bromobenzene (BB) induced hepatotoxicity in the rat when a dose of 2.0 ml/kg is given 24 hr after the toxicants. However, the optimal dose of DMSO and the latest time at which DMSO can be administered and still provide effective protection have not been determined. In order to determine the latest time at which DMSO can interrupt the development of necrosis, male Sprague Dawley rats received either 0.75 ml/kg CHCl3 or 0.5 ml/kg BB, 20% in corn oil, p.o., followed by single dose of 2 ml/kg DMSO, 50% in saline, i.p., at 24, 26, 28 or 30 hr later. Positive control groups received either CHCl3 or BB and then 4.0 ml/kg saline, i.p., 24 hr later. All of the animals were then killed 48 hr after toxicant dosing. The extent of liver injury present when DMSO was administered was examined by killing animals at 24, 26, 28 or 30 hr after toxicant dosing. The optimal dose of DMSO for providing protection was estimated by administering either 0, 1.0, 2.0, 3.0 or 4.0 ml/kg DMSO at 24 hr after toxicant dosing and then killing the animals at 48 hr. Delaying DMSO administration to times later than 24 hr after toxicant dosing led to a loss of protection as indicated by both plasma ALT activity and the light microscopic appearance of liver tissue. The distinctive liver lesions present at 24 hr after CHCl3 or BB dosing rapidly expanded from being limited around central veins to bridging between centrilobular areas in only a few hours. This was accompanied by large increases in plasma ALT. With both toxicants, doses of DMSO greater than 2 ml/kg did not enhance its protective action while the lower dose of 1 ml/kg DMSO was not as effective. The loss of DMSO's antidotal action when given at times later than 24 hr after the toxicants indicates irreversible changes were underway as the centrilobular lesions progressed from being limited to more bridging in nature. Hopefully, further elucidation of the mechanism(s) by which DMSO interrupts the rapid progression of injury will both help to understand the steps involved in lesion development and provide insights into therapeutic interventions for drug and chemical induced hepatitis.
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PMID:Hepatoprotection by dimethyl sulfoxide. II. Characterization of optimal dose and the latest time of administration for effective protection against chloroform and bromobenzene induced injury. 1066 12

Dimethyl sulfoxide (DMSO) has previously been shown to have the ability to attenuate chloroform (CHCl(3))-induced liver injury in the naive rat even when administered 24 h after the toxicant. These studies were undertaken to determine if the protective action by late administration of DMSO is due to an inhibition of the bioactivation of CHCl(3). This was done by comparing the cytochrome P450 inhibitors, diallyl sulfide (DAS), and aminobenzotriazole (ABT) to DMSO for their protective efficacy when administered 24 h after CHCl(3) exposure. In addition, (14)CHCl(3) was utilized to measure the effect of DMSO and ABT on the covalent binding of CHCl(3) in the liver following their late administration. Male Sprague-Dawley rats (300-350 g) received 0.75 ml/kg CHCl(3) po. Twenty-four hours later, they received ip injection of 2 ml/kg DMSO, 100 mg/kg DAS, or 30 mg/kg ABT. Plasma ALT activities and quantitation of liver injury by light microscopy at 48 h after CHCl(3) dosing indicated that all three treatments were equally effective at protecting the liver. A detailed study of the time course of injury development indicated that the protective action of DMSO was occurring within 10 h of its administration. Therefore, in the radiolabel studies, rats were killed 24-34 h after receiving 0.75 ml/kg CHCl(3) (30 microCi/kg (14)CHCl(3)) po. Treatment with ABT at 24 h after (14)CHCl(3) dosing decreased the covalent binding of (14)C to hepatic protein by 35% and reduced the amount of (14)C in the blood by 50% by 10 h after its administration. DMSO treatment did not significantly affect any of these parameters. The lack of effect by late administration of DMSO on the covalent binding of CHCl(3) would indicate that DMSO may offer protection by mechanisms other than inhibition of the bioactivation of CHCl(3). These studies also indicate that specific cytochrome P450 inhibitors may be of benefit in clinical situations to help treat the delayed onset hepatitis that can result following poisoning with an organohalogen, even if the antidotes are administered a number of hours after the initial exposure.
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PMID:Hepatoprotection by dimethyl sulfoxide. III. Role of inhibition of the bioactivation and covalent bonding of chloroform. 1089 56

The dose and time dependence of formation of a specific adduct between mitochondrial phospholipid and phosgene have been determined in the liver of Sprague-Dawley (SD) rats as well as in the liver and kidney of B6C3F1 mice after dosing with chloroform. Rats were induced with phenobarbital or non-induced. Determination of tissue glutathione (GSH) and of serum markers of hepatotoxicity and nephrotoxicity was also carried out. With dose-dependence experiments, a strong correlation between the formation of the specific phospholipid adduct, GSH depletion and organ toxicity could be evidenced in all the organs studied. With non-induced SD rats, no such effects could be induced up to a dose of 740 mg/kg. Time-course studies with B6C3F1 mice indicated that the specific adduct formation took place at very early times after chloroform dosing and was concurrent with GSH depletion. The adduct formed during even transient GSH depletion (residual level: 30% of control) and persisted after restoration of GSH levels. Following a chloroform dose at the hepatotoxicity threshold (150 mg/kg), the elimination of the adduct in the liver occurred within 24 h and correlated with the recovery of ALT, which was slightly increased (12 times) after treatment. Following a moderately nephrotoxic dose (60 mg/kg), the renal adduct persisted longer than 48 h, when a 100% increase in blood urea nitrogen and a 40% increase in serum creatinine indicated the onset of organ damage. The formation of the adduct in the liver mitochondria of B6C3F1 mice was associated with the decrease of phosphatidyl-ethanolamine (PE), in line with previous results in rat liver indicating that the adduct results from the reaction of phosgene with PE. The adduct levels implicated the reaction of phosgene with about 50% PE molecules in the liver mitochondrial membrane of phenobarbital-induced SD rats and of about 10% PE molecules of the inner mitochondrial membrane of the liver of B6C3F1 mice. The association of this adduct with the toxic effects of chloroform makes it a very good candidate as the primary critical alteration in the sequence of events leading to cell death caused by chloroform.
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PMID:Correlation of a specific mitochondrial phospholipid-phosgene adduct with chloroform acute toxicity. 1125 54


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