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)

Data are provided which indicate that pyruvate and/or acetaldehyde can reverse the inhibition of alanine aminotransferase and aspartate aminotransferase by amino-oxyacetate. It was shown that acetaldehyde could reverse the inhibition of gluconeogenesis from alanine and that pyruvate could reverse the inhibition of urea synthesis by amino-oxyacetate.
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PMID:Re-evaluation of amino-oxyacetate as an inhibitor. 84 92

The effects of administration of dec-2-ynol and dec-2-ynoic acid on the hepatic glutathione (GSH) content and hepatic microsomal trans-2-enoyl-CoA reductase activity were examined in rat. Both compounds, when administered ip, caused a marked depletion of GSH levels and a corresponding inactivation of trans-2-enoyl-CoA reductase activity in both a time- and dose-dependent manner. The dec-2-ynoic acid caused greater hepatotoxicity than dec-2-ynol based on serum alanine transaminase activity. Based on the observations that (a) the alcohol did not interact with GSH in the presence or absence of cytosol, (b) the spectral manifestation of the interaction between GSH and the alcohol occurred only when NAD+ was added to the reaction mixture containing the cytosol and reactants, and (c) a similar absorbance spectrum was obtained following the interaction between aldehyde and GSH, it was concluded that dec-2-ynol is converted to an electrophile, dec-2-ynal, which causes depletion of GSH. The decrease in GSH content following administration of the acid appears to be due to activation of the acid to the electrophile, dec-2-ynoyl CoA, which then interacts with GSH, resulting in its depletion, based on the in vitro observations that (a) the acid did not interact with GSH in the presence or absence of cytosol, and (b) the spectral manifestation of interaction between GSH and dec-2-ynoyl CoA occurred both nonenzymatically and enzymatically in the presence of rat liver glutathione S-transferase (Sigma). Bovine serum albumin stimulated the enzymatic reaction. Comparable to the effects on GSH were the effects of dec-2-ynol, dec-2-ynal, dec-2-ynoic acid, and dec-2-ynoyl CoA on the microsomal trans-2-enoyl-CoA reductase activity in vitro. While the alcohol had no effect on the enzyme activity, its electrophilic product, the aldehyde, was a potent inhibitor. Similarly, the acid did not inhibit the enzyme activity unless the acid was present at high concentration; however, its electrophilic product, the CoA thioester, was a very potent inhibitor at very low concentration.
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PMID:Depletion of rat hepatic glutathione and inhibition of microsomal trans-2-enoyl-CoA reductase activity following administration of a dec-2-ynol and dec-2-ynoic acid. 173 41

In vitro models have shown that metabolites of ethanol (acetaldehyde and lactate) stimulate collagen synthesis, thereby, suggesting that they may be important as fibrogenic mediators. The relevance of these findings for fibrogenesis in the human liver in vivo, however, has not as yet been demonstrated. Serum markers for collagen (PIIINP, using radioimmunoassays employing polyclonal antibodies and Fab-fragments (PIIINP-Fab), respectively) and basement membrane (laminin) metabolism were therefore investigated in 25 alcoholic cirrhotics (Pugh-Score: 6.7 +/- 1.9 S.D.) and in 19 comparable nonalcoholic cirrhotics (Pugh-Score: 6.3 +/- 1.5, n.s.) with only slight evidence for inflammation: GOT 28 +/- 22 vs. 24 +/- 21 U/l; GPT 24 +/- 23 vs. 31 +/- 28 U/l; gamma-globulins 24 +/- 8 vs. 22 +/- 5%, respectively (all n.s.). Severity of the disease was assessed by quantitative liver function tests. Levels of PIIINP, PIIINP-Fab and laminin measured by RIA were 21 +/- 19 micrograms/l, 90 +/- 42 micrograms/l and 2.5 +/- 0.8 U/ml in alcoholic cirrhosis and 10 +/- 6 micrograms/l, 61 +/- 10 micrograms/l and 1.9 +/- 0.4 U/ml in nonalcoholic cirrhosis, respectively (all p less than 0.01). Differences on PIIINP and PIIINP-Fab remained significant even after accurate matching for galactose elimination capacity, aminopyrine breath test and hepatic sorbitol clearance. Laminin levels were higher in alcoholic cirrhosis only after matching for the hepatic sorbitol clearance (p less than 0.01). The higher levels of serum markers for collagen and basement membrane metabolism in alcoholic vs. nonalcoholic patients with cirrhosis at equal severity of the disease and with only minimal signs of inflammation may be the clinical reflection of a specific fibrogenic effect of ethanol metabolites.
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PMID:Higher levels of serum aminoterminal type III procollagen peptide, and laminin in alcoholic than in nonalcoholic cirrhosis of equal severity. 173 19

Significance of the antibody to alcohol altered hepatocyte plasma membrane (AAHM) was studied in various types of alcoholic liver diseases (ALD). AAHM was detected in the sera that were collected within 3 months of alcohol abstinence from patients with various types of ALD, with higher frequency in alcoholic hepatitis and cirrhosis. Serum acetaldehyde, gamma-globulin fraction, immunoglobulin A and G were higher in patients positive for AAHM, though the levels of GOT, GPT, mGOT were indifferent of the existence of AAHM. Histologically, hepatocyte ballooning and pericellular fibrosis were frequently seen in patients positive for AAHM, but close relationship between the extent of necrosis and existence of AAHM was not observed. These findings suggest that the occurrence of AAHM is closely related with the functional and morphological changes of the hepatocyte induced by acetaldehyde but not with hepatocyte necrosis.
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PMID:[Study of the antibody to alcohol altered hepatocyte plasma membrane in alcoholic patients]. 222 84

To better define the significance and mechanism of acetaldehyde-mediated transaminase inhibition, acetaldehyde metabolism was studied in rat liver homogenates and cytosols. When either preparation was incubated at 37 degrees with 1.5 mM acetaldehyde for 4 hr, acetaldehyde levels fell rapidly in the first 30 min and little inhibition of aspartate aminotransferase (GOT) or alanine aminotransferase (GPT) resulted. In contrast, incubation with 50 mM ethanol also resulted in a peak acetaldehyde level of 1.0 to 1.5 mM by 2 hr, but this level was then maintained for the next 2 hr and transaminases were inhibited by 20-35%. Sequential addition of low dose (125-250 microM) pulses of acetaldehyde to rat liver preparations resulted in a progressive decrease in the rate of acetaldehyde disappearance. When the pulsing schedule was adjusted accordingly to maintain acetaldehyde levels between 50 and 250 microM for 8 hr, transaminases were again inhibited by 20-40%. Finally, addition of 1-5 mM pyridoxal and pyridoxal 5'-phosphate, aldehydic B6 vitamers, to cytosols 2-4 hr after pulsing with acetaldehyde was begun, almost completely prevented further transaminase inhibition. In contrast, the non-aldehydic B6 vitamers, pyridoxine, pyridoxamine and pyridoxamine 5'-phosphate, did not affect acetaldehyde-mediated transaminase inhibition. These findings suggest that (1) prolonged exposure to low levels of acetaldehyde impairs acetaldehyde metabolism in rat liver homogenates and cytosols; (2) acetaldehyde toxicity may be more dependent on sustained exposure to acetaldehyde than on the peak level of acetaldehyde attained; and (3) aldehydic B6 vitamers can modify on-going acetaldehyde-mediated transaminase inhibition.
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PMID:Inhibition of rat liver transaminases by low levels of acetaldehyde and the pharmacologic effects of B6 vitamers. 281 34

4-Hydroxynonenal (HNE), a major aldehyde end-product of lipid peroxidation, induces in vitro a rapid stimulation of rat liver PIP2-phospholipase C. At physiological Ca2+ concentration the effect of the aldehyde is strongly potentiated by guanosine thiotriphosphate (GTP gamma S); GPT gamma S; at higher Ca2+ levels the acceleration of PIP2 breakdown induced by the aldehyde reaches very high values, but is no longer modulated by the presence of GTP gamma S. As the concentration of the aldehyde used (1 micromolar) can be actually reached in tissues, the effects shown in vitro are likely to occur in vivo.
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PMID:Stimulation of phospholipase C activity by 4-hydroxynonenal; influence of GTP and calcium concentration. 325 Sep 44

Since red cells transport and metabolize acetaldehyde in vivo, the effects of acetaldehyde on human red cell enzyme activities were studied. Incubation of intact red cells or undiluted red cell lysates at 37 degrees C for 4 h with 1-10 mmol/l acetaldehyde decreased only GOT, GPT and aldolase activities among the 26 enzymes tested. No inhibition occurred at 4 degrees C or when acetaldehyde was incubated with dilute hemolysates. Incubation of lysates with other reducing substrates or with acetate inhibited aldolase but not GOT or GPT. Preincubation of lysates with cyanate or fluoride markedly decreased acetaldehyde-mediated transaminase inhibition but not aldolase inhibition. Addition of pyridoxal phosphate, the vitamin B6 transaminase coenzyme, to GOT and GPT assay mixes did not reverse acetaldehyde-mediated transaminase inhibition. These findings suggest that acetaldehyde-mediated aldolase inhibition results from oxidation of acetaldehyde while transaminase inhibition results from nonoxidative acetaldehyde metabolism. When 100-200 mumol/l acetaldehyde is added to lysates at 2-h intervals and when lysates are incubated with ethanol, alcohol dehydrogenase and an NAD-regenerating system, enzyme inhibition occurs at acetaldehyde levels approaching those seen in vivo. Thus, the role of acetaldehyde-mediated enzyme inhibition in the toxicity of alcohol abuse warrants further study.
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PMID:Effects of acetaldehyde on human red cell metabolism: evidence for the formation of enzyme inhibitors. 341 86

Since ethanol consumption decreases hepatic aminotransferase activities in vivo, mechanisms of ethanol-mediated transaminase inhibition were explored in vitro using mitochondria-depleted rat liver homogenates. When homogenates were incubated at 37 degrees with 50 mM ethanol for 1 hr, alanine aminotransferase decreased by 20%, while aspartate aminotransferase was unchanged. After 2 hr, aspartate aminotransferase decreased by 20% and by 3 hr, alanine and aspartate aminotransferases were decreased by 31 and 23%, respectively. Levels of acetaldehyde generated during ethanol oxidation were 525 +/- 47 microM at 1 hr, 855 +/- 14 microM at 2 hr, and 1293 +/- 140 microM at 3 hr. Although inhibition of alcohol oxidation with methylpyrazole or cyanide markedly decreased ethanol-mediated transaminase inhibition, neither incubation with acetate nor generation of reducing equivalents by oxidation of lactate, malate, xylitol, or sorbitol altered the activity of either enzyme. However, semicarbazide, an aldehyde scavenger, prevented inhibition of both aminotransferases by ethanol. Moreover, incubation with 5 mM acetaldehyde for 1 hr inhibited alanine and aspartate aminotransferases by 36 and 26%, respectively. Cyanamide, an aldehyde dehydrogenase inhibitor, had little effect on ethanol-mediated transaminase inhibition. Thus, metabolism of ethanol by rat liver homogenates produces transaminase inhibition similar to that described in vivo and this effect requires acetaldehyde generation but not acetaldehyde oxidation. Since addition of pyridoxal 5'-phosphate to assay mixes did not reverse ethanol effects, aminotransferase inhibition does not result from displacement of vitamin B6 coenzymes.
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PMID:Evidence for the generation of transaminase inhibitor(s) during ethanol metabolism by rat liver homogenates: a potential mechanism for alcohol toxicity. 366 1

The effects of the cyclodiene pesticide, endrin, and its aldehyde and ketone metabolites on hepatobiliary function and CCl4-induced hepatotoxicity were investigated in Sprague-Dawley rats. The rats were given control diet or diets containing 5 or 10 ppm endrin, 10 ppm endrin aldehyde or 5 ppm endrin ketone for 15 days. Three to six rats from each treatment group were given a single ip dose (100 microliter/kg body weight) of CCl4 in corn oil (1 ml/kg) on day 15. Levels of serum glutamic-oxalacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), isocitrate dehydrogenase and ornithine-carbamyl transferase, bile flow and biliary excretion of an anionic model compound, phenolphthalein glucuronide (PG), were measured on day 16. Dietary treatment with endrin at either dose level did not significantly elevate serum enzyme levels, while endrin aldehyde produced a slight increase in SGOT and SGPT and endrin ketone produced a small elevation in SGPT levels. Treatment with endrin aldehyde or endrin ketone did not result in significant alterations of bile flow or biliary PG excretion. Treatment with 5 ppm endrin produced a significant reduction in bile flow and a corresponding reduction in PG excretion by male rats, whereas treatment with 10 ppm endrin reduced only the PG excretion by male rats. Female rats treated with 5 or 10 ppm endrin showed a dose-dependent choleretic effect with a commensurate increase in PG excretion. With the exception of a further slight reduction in PG excretion by male rats, treatment with the endrin or endrin derivative did not potentiate CCl4-induced alterations in hepatobiliary functions. Although the levels of some serum enzymes of rats given endrin or endrin derivatives plus CCl4 were elevated over those of rats given CCl4 alone, the increases were not of the magnitude of those that have been reported previously for chlordecone. Generally, female rats challenged with CCl4 or endrin/CCl4 exhibited greater increases in serum enzyme levels than did male rats given corresponding treatments.
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PMID:Effect of endrin and endrin derivatives on hepatobiliary function and carbon tetrachloride-induced hepatotoxicity in male and female rats. 378 35

Ethanol metabolism in rat hepatocytes isolated either from the periportal (pp) or the perivenous (pv) area by collagenase gradient perfusion was compared to reveal metabolic factors that could be associated with the development of perivenous alcoholic liver damage. Cells were also isolated from rats given ethanol (E) chronically by addition to the drinking fluid. One group (EM) received in addition the alcohol dehydrogenase inhibitor 4-methylpyrazole, which potentiated the ethanol treatment by causing sustained elevated diurnal blood ethanol levels. Fatty degeneration ensued in only one-third of the E rats but in all of the EM rats. The periportal/perivenous activity distributions of alanine aminotransferase (ALAT) and glutamate dehydrogenase (GLDH) were 2.2 and 0.75, respectively. Both ethanol treatments significantly decreased the ALAT and increased the GLDH activities, but did not change their pp/pv distributions. Ethanol treatment also increased ethanol and acetaldehyde oxidation, but to the same extent in pp and pv cells. The increase was more marked in cells from EM rats despite their more severe liver fatty degeneration. Ethanol incubation also increased the lactate/pyruvate ratio to the same extent in pp and pv cells both from control or ethanol-treated rats. Our results indicate that periportal and perivenous hepatocytes convert ethanol via acetaldehyde to acetate equally well and with similar effects even after chronic ethanol treatment. Consequently, preferential damage of the perivenous area after chronic ethanol intake is not caused by inherent or acquired differences in ethanol metabolism between perivenous and periportal hepatocytes. Rather, sinusoidal gradients only established in the intact liver may exaggerate the metabolic imbalance by ethanol in the perivenous area, thus explaining its greater vulnerability to damage by alcohol abuse.
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PMID:Comparison of ethanol metabolism in isolated periportal or perivenous hepatocytes: effects of chronic ethanol treatment. 390


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