| Metabolism of gamma-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase. | |
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MedLine Citation:
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PMID: 16483879 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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gamma-Hydroxybutyratic acid (GHB), and its prodrugs 4-butyrolactone and 1,4-butanediol, represent expanding drugs of abuse, although GHB is also used therapeutically to treat narcolepsy and alcoholism. Thus, the pathway by which GHB is metabolized is of importance. The goal of the current study was to examine GHB metabolism in mice with targeted ablation of the GABA degradative enzyme succinic semialdehyde dehydrogenase (SSADH(-/-) mice), in whom GHB persistently accumulates, and in baboons intragastrically administered with GHB immediately and persistently. Three hypotheses concerning GHB metabolism were tested: (1) degradation via mitochondrial fatty acid beta-oxidation; (2) conversion to 4,5-dihydroxyhexanoic acid (a putative condensation product of the GHB derivative succinic semialdehyde); and (3) conversion to d-2-hydroxyglutaric acid (d-2-HG) catalyzed by d-2-hydroxyglutarate transhydrogenase (a reaction previously documented only in rat). Both d-2-HG and 4,5-dihydroxyhexanoic acid were significantly increased in neural and nonneural tissue extracts derived from SSADH(-/-) mice. In vitro studies demonstrated the ability of 4,5-dihydroxyhexanoic acid to displace the GHB receptor ligand NCS-382 (IC(50) = 38 micromol/L), although not affecting GABA(B) receptor binding. Blood and urine derived from baboons administered with GHB also accumulated d-2-HG, but not 4,5-dihydroxyhexanoic acid. Our results indicate that d-2-HG is a prominent GHB metabolite and provide further evidence for the existence of d-2-hydroxyglutarate transhydrogenase in different mammalian species. |
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Authors:
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Eduard A Struys; Nanda M Verhoeven; Erwin E W Jansen; Herman J Ten Brink; Maneesh Gupta; Terry G Burlingame; Lawrence S Quang; Timothy Maher; Piero Rinaldo; O Carter Snead; Amy K Goodwin; Elise M Weerts; P Rand Brown; Tonya C Murphy; Mathew J Picklo; Cornelius Jakobs; K Michael Gibson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Metabolism: clinical and experimental Volume: 55 ISSN: 0026-0495 ISO Abbreviation: Metab. Clin. Exp. Publication Date: 2006 Mar |
Date Detail:
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Created Date: 2006-02-17 Completed Date: 2006-06-05 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0375267 Medline TA: Metabolism Country: United States |
Other Details:
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Languages: eng Pagination: 353-8 Citation Subset: IM |
Affiliation:
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Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Alcohol Oxidoreductases* Animals Glutarates / analysis, metabolism* Kinetics Mammals Mice Mice, Knockout Papio Sodium Oxybate / metabolism* Succinate-Semialdehyde Dehydrogenase / deficiency |
| Grant Support | |
ID/Acronym/Agency:
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DA14919/DA/NIDA NIH HHS; DA14951/DA/NIDA NIH HHS; NS40270/NS/NINDS NIH HHS; P20 RR17699/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Glutarates; 2889-31-8/alpha-hydroxyglutarate; 502-85-2/Sodium Oxybate; EC 1.1.-/Alcohol Oxidoreductases; EC 1.1.99.24/hydroxyacid-oxoacid transhydrogenase; EC 1.2.1.24/Succinate-Semialdehyde Dehydrogenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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