| The role of retinoid X receptor alpha in regulating alcohol metabolism. | |
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MedLine Citation:
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PMID: 16829625 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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There is substantial overlap in retinol and alcohol metabolism. Mice that lack retinoic acid (RA) receptor retinoid X receptor alpha (RXRalpha) expression in the liver are more susceptible to alcoholic liver disease. To investigate the interaction between RXRalpha and alcoholic liver disease, ethanol metabolism was studied in hepatocyte RXRalpha-deficient [RXRalpha knockout (KO)] mice. Hepatocyte RXRalpha deficiency resulted in a significant increase in hepatic alcohol dehydrogenase (ADH) activity, ADH1 protein, but not Adh1 mRNA. Polysomal distribution analysis indicated that more polysome-associated Adh1 mRNA was present in the mutant mouse livers, suggesting increased ADH1 protein synthesis in RXRalpha KO mice compared with wild-type mice. However, ADH2 and ADH3 enzyme activities were not affected by RXRalpha deficiency. Although ethanol clearance was increased, acetaldehyde elimination was reduced when RXRalpha was not expressed in the liver. Both mitochondrial aldehyde dehydrogenase (ALDH) 2 and cytosolic ALDH activities were reduced in the mutant mice compared with the wild type. Western blot analysis revealed that the levels of ALDH1A1 and ALDH1A2 were decreased in the mutant mice. Semiquantitative reverse transcriptase-polymerase chain reaction indicated that liver Aldh1a1 mRNA level was also reduced due to the lack of RXRalpha expression. Thus, RXRalpha differentially affects ADH and ALDH activity, leading to an increase in alcohol clearance, but a reduction in acetaldehyde elimination. In addition, CYP2E1 as well as mitochondrial and cytosolic glutathione S-transferase activities were significantly lower in RXRalpha KO mice than in wild-type mice. Our results reveal the central role of RXRalpha in ethanol metabolism. |
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Authors:
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Maxwell Afari Gyamfi; Michael George Kocsis; Lin He; Guoli Dai; Alphonse John Mendy; Yu-Jui Yvonne Wan |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2006-07-07 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 319 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2006 Oct |
Date Detail:
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Created Date: 2006-09-26 Completed Date: 2006-11-02 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 360-8 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alcohol Dehydrogenase
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genetics Animals Cytochrome P-450 CYP2E1 / physiology Ethanol / metabolism* Isoenzymes / genetics Mice Mice, Knockout RNA, Messenger / analysis Retinoid X Receptor alpha / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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AA14147/AA/NIAAA NIH HHS; CA53596/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Isoenzymes; 0/RNA, Messenger; 0/Retinoid X Receptor alpha; 64-17-5/Ethanol; EC 1.1.1.1/Alcohol Dehydrogenase; EC 1.14.14.1/Cytochrome P-450 CYP2E1 |
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