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)

Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.
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PMID:Mechanistic studies of the inhibition of hepatic uroporphyrinogen decarboxylase in C57BL/10 mice by iron-hexachlorobenzene synergism. 380 Sep 66

Cobalt-activated acylase (Co-A) and transaminase activity were determined in the serum of A/Jax, DBA/2 and C3H mice several days after an intraperitoneal injection of 1,000 lethal doses of murine hepatitis virus type 3 (MHV3). A significant rise in the enzyme activity was observed 1 day after the injection, followed by a decrease on day 2. In the case of the genetically resistant A/Jax strain, the Co-A level regularly decreased to reach normal values on days 7-8. On the contrary, among the fully susceptible DBA/2 strain mice (all dead on day 5), a second rise in acylase (Co-A) level was observed on days 3 and 4, much higher than the day-1 values. Among the mice of C3H strain, which is recorded as 'semi-susceptible', some individuals behaved like the susceptible DBA/2. The comparison of serum acylase activity with other liver function tests showed a correlation between Co-A and transaminases (ALT and AST) with C3H and DBA/2 strains, but no correlation with A/JAX resistant strain. gamma-Glutamyltransferase was not detectable in the serum of different strains during the time of experimentations. Our results suggest that Co-A activity correlates with the clinical course, and that Co-A is a sensitive indicator enzyme in the early phase of viral hepatitis.
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PMID:A genetic study of serum levels of cobalt-activated acylase among susceptible, resistant and semiresistant strains of mice with experimental viral hepatitis. 715 76

Erythrocyte aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities are often used as indices of vitamin B-6 nutritional status; however, results using a mixed population of erythrocytes can be quite variable. Erythrocytes from two strains of mice (Mus domesticus), A/Ibg and DBA/Ibg, were separated according to age by centrifugation through discontinuous Percoll density gradients into three fractions: top (least dense, youngest), middle and bottom (most dense, oldest). A sufficient yield of age-fractionated erythrocytes was obtained from a single mouse for all of the enzyme measurements. The activities of AST, ALT and three age-marker enzymes, pyruvate kinase, acetylcholinesterase and hexokinase, were found to be significantly higher in the youngest cell fractions, and declined in the older, more dense fractions. A mice had significantly lower AST and ALT activities in the age separated fractions than did DBA mice. The measurement of enzyme activities in low density, young cells may be especially useful in studies involving conditions in which the proportion of young erythrocytes may be elevated with respect to the entire erythrocyte mass.
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PMID:Aminotransferase activities in mouse, Mus domesticus, erythrocytes separated according to age. 755 57

Cocaine is reported to produce either periportal or mid-zonal necrosis in mice pretreated with the enzyme inducer phenobarbitone (James et al. 1987; Powell et al. 1991; Charles & Powell 1992). Dose-response and time course experiments were performed in phenobarbitone treated male DBA/2Ha mice to study the pathogenesis of this unusual cocaine induced lesion. An increase in the dose of cocaine from 60 to 90 or 120 mg/kg produced more extensive and severe periportal and linking portal damage and elevated plasma aspartate (AST) and alanine (ALT) aminotransferases in a dose dependent manner. Scattered hepatocyte degeneration began at the edge of the periportal region and was detectable by electron microscopy within 30 minutes of administration of 60 mg/kg of cocaine, with conspicuous disorganization of the endoplasmic reticulum being one of the earliest changes. Significant elevations of plasma AST and ALT were observed 3 hours after cocaine administration and were sustained for 12 hours, at which time progressive hepatocyte damage had developed into a network of confluent necrosis at the periphery of the periportal region. The rapidity of organelle derangement and subsequent cell death, and absence of any effect on total cytochrome P-450 or FAD-mono-oxygenase levels, appear to distinguish this periportal lesion from previous reports of cocaine induced centrilobular necrosis in non-enzyme induced mice, suggesting that the two types of damage may develop by different mechanisms. The observation that periportal lesions commence at the periphery of the periportal area, progressing portalwards with increasing dose and time, offers an explanation for the previously conflicting reports of cocaine induced mid-zonal and/or periportal lesions in phenobarbitone treated mice.
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PMID:Cocaine hepatotoxicity: a study on the pathogenesis of periportal necrosis. 773 31

Cocaine is eliminated and detoxified principally through the metabolism of nonspecific plasma and tissue esterases. Microsomal oxidative metabolism is of importance in cocaine N-demethylation, this being a principal pathway of cocaine bioactivation and hepatotoxicity. The contribution of different cytochrome P450 (CYP) enzymes to cocaine N-demethylase activity was studied in vitro with DBA/2 mouse and human liver microsomes, and cocaine hepatotoxicity was examined in vivo in DBA/2 male mice. Species dependent enzyme kinetics was observed. Cocaine N-demethylase displayed two Km values in murine liver (40-60 microM and 2-3 mM), whereas only one Km value was observed in human liver microsomes (2.3-2.7 mM). We suggest that CYP3A plays a prominent role in the N-demethylation of cocaine for the following reasons: (i) pregnenolone-16 alpha-carbonitrile, an inducer of CYP3As increases cocaine N-demethylase in parallel with testosterone 6 beta-hydroxylase activity and immunoreactive 3A protein in mouse liver; (ii) human and mouse cocaine N-demethylase and testosterone 6 beta-hydroxylase activities can be inhibited by triacetyloleandomycin, cannabidiol, or gestodene, all selective inhibitors of CYP3A P450s; (iii) antibodies directed against P450s within subfamilies 1A, 2A, 2B, 2C, or 2E inhibited cocaine N-demethylase activity only marginally, and finally, (iv) treatment of mice with triacetyloleandomycin or cannabidiol in vivo significantly attenuated the cocaine-elicited hepatotoxicity as assessed by the serum alanine aminotransferase activity and liver histology in parallel with decreased cocaine N-demethylase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors. 815 80

Nine inbred strains of mice, which are progenitors of recombinant inbred sets, were evaluated for aortic lesion formation and plasma and liver lipid levels. This survey was done to determine if a semi-synthetic high-fat diet could elicit the same extent of diet-induced atherosclerosis as that observed in mice fed a natural ingredient high-fat diet and to discover strain-specific plasma and liver lipid variants for future genetic characterization. Evaluation of aortic lesions after 18 wk of diet consumption showed that strains C57BL/6J, C57L/J, SWR/J and SM/J were susceptible to atherosclerosis and that A/J, AKR/J, C3H/HeJ, DBA/2J and SJL/J were relatively resistant. High-density lipoprotein cholesterol (HDL-C) levels were negatively correlated to lesion formation. Susceptible strains had decreased HDL-C levels when switched from chow to the semi-synthetic high-fat, high cholesterol diet, whereas resistant strains either showed no change or a slight increase in HDL-C levels. The exception to this pattern was found in SM mice, which were susceptible to aortic lesion formation but maintained the same HDL-C level on both chow and high-fat diets. HDL size differed among the strains, and levels of plasma apolipoprotein A-I and A-II correlated with HDL-C levels. Liver damage was not correlated to HDL-C levels or to susceptibility to atherosclerosis. Mice from strain A, which are resistant to atherosclerosis, had evidence of liver damage as observed by elevated levels of plasma alanine aminotransferase activity, by liver histology, by increased liver weight and by exceptionally high hepatic cholesterol content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atherosclerosis and plasma and liver lipids in nine inbred strains of mice. 835 88

Two gold compounds, gold sodium thiomalate (AuTM) and auranofin, are presently in clinical use in therapy of rheumatoid arthritis. In these studies, AuTM administered to Sprague-Dawley rats and three strains of mice, Swiss-Webster, C3H/HeJ, and DBA/2J, were studied with regard to its effect on liver and renal monooxygenases, metallothionein contents, and serum levels of alanine aminotransferase and urea nitrogen. These effects of AuTM were compared to those of cadmium, since the latter metal has exhibited tissue and species differences in the induction of metallothionein. Benzo(a)pyrene hydroxylase and benzphetamine N-demethylase activities were not altered by AuTM in livers of rats and the three strains of mice. Benzo(a)pyrene hydroxylase activity was significantly decreased in rat kidney, whereas this enzyme activity was not affected in the kidneys of mice. In rats, AuTM caused a sevenfold induction in liver metallothionein, while in mice, liver metallothionein was induced twofold in Swiss-Webster mice and about fivefold in the inbred strains. AuTM caused minimal changes in renal metallothionein contents in the three strains of mice studied. Serum alanine amino-transferase, an indicator of hepatotoxicity, was not altered by AuTM in rats and mice studied. Blood urea nitrogen, an indicator of kidney dysfunction, was increased threefold in rats, but not in AuTM-treated mice. These data demonstrate that AuTM, a nephrotoxic agent in rats and humans, showed no nephrotoxic effects in the mouse strains studied here.
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PMID:Species differences in the renal toxicity of the antiarthritic drug, gold sodium thiomalate. 906 47

Treatment with a combination of 10 mg/kg i.p. methotrexate and 100 mg/kg i.p. nicotinamide inhibits the development of collagen II induced arthritis in male DBA/1 X B.10(4R) mice, as assessed by the arthritic index and whole blood chemiluminescence. The effect is much more pronounced than with either methotrexate or nicotinamide alone at the same concentrations. Determination of GOT and GPT levels in the blood revealed that the treatment causes no toxic side effects on the liver.
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PMID:Enhancement of the effect of methotrexate on collagen II induced arthritis in mice by nicotinamide. 960 15

The alpha-class glutathione S-transferases are proposed to play a prominent role in catalyzing the conjugation of glutathione with electrophilic aldehydic products of lipid peroxidation. The effect of iron-induced lipid peroxidation on induction of glutathione S-transferase (GST) isozymes A1 and A4 in the livers of male C57/BL6Ibg and DBA/J2Ibg mice was studied. C57 and DBA mice were fed for 4 months on a diet supplemented with iron as ferrocene and then were assessed for liver injury, hepatic iron loading, indices of lipid peroxidation, GST activity, and induction of GST isozymes A1 and A4. Iron-treated animals displayed a loss in body weight from pair-fed controls and had large increases in hepatic non-heme iron with concomitant liver injury, as measured by serum alanine aminotransferase. Hepatic lipid hydroperoxides, a direct measure of oxidized membrane lipids, were significantly increased only in C57 mice, but hepatic concentrations of reduced glutathione (GSH) were significantly increased in both inbred strains. Total GST activity toward 1-chloro-2,4-dinitrobenzene was significantly increased in C57 mice but not in DBA. Western blot studies using polyclonal antibodies specific for GST A1 and A4 revealed significant increases of 1.5-2.0-fold in these GST isoforms in both inbred strains. These results in a unique murine model for hepatic iron overload further support recent in vivo studies (Khan et al., Toxicol. Appl. Pharmacol., 131, 63-72, 1995) that have associated induction of GST A4 with protection against oxidative stress-induced lipid peroxidation. The observed increases in lipid hydroperoxides, hepatic GSH, GST activity, and GST A1 and A4 protein strongly support the hypothesis that induction of GST A1 and A4 represents an important protective event in the detoxification of electrophilic products of lipid peroxidation.
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PMID:Association of glutathione S-transferase isozyme-specific induction and lipid peroxidation in two inbred strains of mice subjected to chronic dietary iron overload. 970 1

Replication-deficient adenoviruses are known to induce acute injury and inflammation of infected tissues, thus limiting their use for human gene therapy. However, molecular mechanisms triggering this response have not been fully defined. To characterize this response, chemokine expression was evaluated in DBA/2 mice following the intravenous administration of various adenoviral vectors. Administration of adCMVbeta gal, adCMV-GFP, or FG140 intravenously rapidly induced a consistent pattern of C-X-C and C-C chemokine expression in mouse liver in a dose-dependent fashion. One hour following infection with 10(10) PFU of adCMVbeta gal, hepatic levels of MIP-2 mRNA were increased >60-fold over baseline. MCP-1 and IP-10 mRNA levels were also increased immediately following infection with various adenoviral vectors, peaking at 6 hr with >25- and >100-fold expression, respectively. Early induction of RANTES and MIP-1beta mRNA by adenoviral vectors also occurred, but to a lesser degree. The induction of chemokines occurred independently of viral gene expression since psoralen-inactivated adenoviral particles produced an identical pattern of chemokine gene transcription within the first 16 hr of administration. The expression of chemokines correlated as expected with the influx of neutrophils and CD11b+ cells into the livers of infected animals. At high titers, all adenoviral vectors caused significant hepatic necrosis and apoptosis following systemic administration to DBA/2 mice. To investigate the role of neutrophils in this adenovirus-induced hepatic injury, animals were pretreated with neutralizing anti-MIP-2 antibodies or depleted of neutrophils. MIP-2 antagonism and neutrophil depletion both resulted in reduced serum ALT/AST levels and attenuation of the adenovirus-induced hepatic injury histologically, confirming that this early injury is largely due to chemokine production and neutrophil recruitment. Our findings further clarify the early immune response against replication-deficient adenoviral vectors and suggest a strategy to prevent adenovirus-mediated inflammation and tissue injury by interfering with chemokine or neutrophil function.
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PMID:Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. 1022 30


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