Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1332347 (ADH)
 2,230 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To assess the importance of non-ADH ethanol metabolism, ADH-negative and ADH-positive deermice were fed liquid diets containing ethanol or isocaloric carbohydrate for 2-4 weeks. Blood ethanol disappearance rate increased significantly after chronic ethanol feeding in both strains. Although at low ethanol concentrations (between 5 and 10 mM) there was no significant difference between ethanol-fed and pair-fed control animals, at high ethanol concentrations (between 40 and 70 mM) blood ethanol elimination rates were increased significantly after chronic ethanol feeding in both ADH-positive and ADH-negative animals. There was no significant effect of the catalase inhibitor 3-amino-1,2,4-triazole on the ethanol elimination/rates in both strains. Whereas catalase and ADH activities were not altered after chronic ethanol treatment, the activity of the microsomal ethanol-oxidizing system (MEOS) was enhanced three to four times in both strains, and microsomal cytochrome P-450 content was also increased significantly. When MEOS activity was expressed per cytochrome P-450 content, it was higher in ADH-negative than in ADH-positive animals, and it increased after ethanol administration. When microsomal proteins were separated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, ethanol-fed animals had a distinct band which reflected the increase in microsomal cytochrome P-450 content and seemed to reflect a unique form of cytochrome P-450 induced by ethanol. Thus, despite the absence of the ADH pathway, a large amount of ethanol was metabolized by MEOS in ADH-negative deermice; this was associated with increased blood ethanol elimination rates, enhanced MEOS activity, and quantitative and qualitative changes of cytochrome P-450.
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PMID:Ethanol metabolism in vivo by the microsomal ethanol-oxidizing system in deermice lacking alcohol dehydrogenase (ADH). 637 Feb 62

Several studies in our unit showed that in men, baboons, rats and deermice, blood ethanol clearance is significantly accelerated at ethanol concentrations higher than the levels needed to effectively saturate the low Km forms of ADH present in animals, thereby incriminating a high Km non-ADH system such as microsomal ethanol oxidizing system (MEOS). Furthermore, kinetics of blood ethanol clearance were consistent with the Km of MEOS. After chronic ethanol consumption, there was an increase in rates of ethanol elimination and in the activity of MEOS. There was an associated rise in microsomal cytochrome P-450, including a form (different from that of a non-ADH pathway of ethanol metabolism and its increase after chronic ethanol consumption was most conclusively shown in ADH-negative deermice. Microsomal induction was also associated with enhanced metabolism of other drugs, resulting in metabolic drug tolerance. In addition, there was increased activation of known hepatotoxic agents (such as CCl4 and acetaminophen) which may explain the enhanced susceptibility of alcoholics to the toxicity of solvents and commonly used drugs. There was enhanced activation of procarcinogens, sometimes at concentrations much lower than those required for other microsomal inducers. Moreover, catabolism of retinoic acid was accelerated possibly contributing to hepatic vitamin A depletion. In conclusion, after chronic ethanol consumption, enhanced MEOS activity and concomitant cytochrome P-450 changes may contribute to accelerated ethanol and drug metabolism and associated activation of hepatotoxic agents and carcinogens.
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PMID:Microsomal ethanol oxidizing system (MEOS): interaction with ethanol, drugs and carcinogens. 641 69

It is well known that acetaldehyde is capable of covalent binding to liver proteins. However, in experiments using liver microsomes prepared from chronically ethanol-fed rats we have observed that the addition of EDTA-iron complex to the microsomes increases by about 4-5 fold both the spin trapping of hydroxyethyl radicals and the covalent binding of 14C-ethanol to proteins, while it only doubles acetaldehyde formation. Conversely, the presence of GSH strongly decreases the trapping of hydroxyethyl radicals and completely inhibits the covalent binding, without affecting acetaldehyde production. Furthermore, the spin trapping agent 4-pyridyl-N-oxide-t-butyl nitrone (4-POBN), previously employed for the detection of hydroxyethyl radicals, decreases by about 70% the covalent binding of 14C-ethanol to microsomal proteins. 4-POBN does not affect acetaldehyde production by liver microsomes, nor does it interfere with the covalent binding of acetaldehyde produced by ADH-mediated oxidation of ethanol. The results obtained indicate that hydroxyethyl radicals generated during ethanol oxidation by cytochrome P-450 play an important role in the alkylation of microsomal proteins consequent to ethanol metabolism.
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PMID:Evidence for the covalent binding of hydroxyethyl radicals to rat liver microsomal proteins. 839 27

This article represents the proceedings of a symposium at the 2004 RSA Meeting held in Vancouver, Canada. The chairs were Arthur I. Cederbaum and Raj Lakshman. The presentations were (1) ethanol regulates 2,6-sialyltransferase (2,6-ST) gene expression posttranscriptionally by the interaction of a cytosolic binding protein with 2,6-ST mRNA in CYP2E1- and ADH-transfected HepG2 cells, by Raj Lakshman; (2) nature versus nurture: HepG2-E47 cells as a tool to investigate mechanisms of ethanol-mediated potentiation of cell killing, by Jan B. Hoek; (3) ethanol up-regulates profibrogenic connective tissue growth factor gene expression in HepG2 cells via cytochrome P-450 2E1-mediated ethanol oxidation, by Masahiro Konishi; (4) role of calcium and calcium-activated enzymes in CYP2E1-dependent toxicity, by Arthur I Cederbaum; (5) the use of cell lines to characterize the role of CYP2E1 in the metabolism of farnesol, by Dennis Koop; and (6) studies with HepG2 cells that express the two major ethanol-metabolizing enzymes, by Terrence M. Donohue.
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PMID:Use of CYP2E1-transfected human liver cell lines in elucidating the actions of ethanol. 1620 73

Trichloroethylene (TCE) is a widely used organic solvent. Although TCE is classified as carcinogenic to humans, substantial gaps remain in our understanding of interindividual variability in TCE metabolism and toxicity, especially in the liver. A hypothesis was tested that amounts of oxidative metabolites of TCE in mouse liver are associated with hepatic-specific toxicity. Oral dosing with TCE was conducted in subacute (600 mg/kg/d; 5 d; 7 inbred mouse strains) and subchronic (100 or 400 mg/kg/d; 1, 2, or 4 wk; 2 inbred mouse strains) designs. The quantitative relationship was evaluated between strain-, dose-, and time-dependent formation of TCE metabolites from cytochrome P-450-mediated oxidation (trichloroacetic acid [TCA], dichloroacetic acid [DCA], and trichloroethanol) and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione] in serum and liver, and various hepatic toxicity phenotypes. In subacute study, interstrain variability in TCE metabolite amounts was observed in serum and liver. No marked induction of Cyp2e1 protein levels in liver was detected. Serum and hepatic levels of TCA and DCA were correlated with increased transcription of peroxisome proliferator-marker genes Cyp4a10 and Acox1 but not with degree of induction in hepatocellular proliferation. In subchronic study, serum and liver levels of oxidative metabolites gradually decreased over time despite continuous dosing. Hepatic protein levels of CYP2E1, ADH, and ALDH2 were unaffected by treatment with TCE. While the magnitude of induction of peroxisome proliferator-marker genes also declined, hepatocellular proliferation increased. This study offers a unique opportunity to provide a scientific data-driven rationale for some of the major assumptions in human health assessment of TCE.
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PMID:Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: liver effects. 2542 44


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