Metabolism of γ-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase

Struys, Eduard A.; Verhoeven, Nanda M.; Jansen, Erwin E.W.; ten Brink, Herman J.; Gupta, Maneesh; Burlingame, Terry G.; Quang, Lawrence S.; Maher, Timothy; Rinaldo, Piero; Snead, O. Carter; Goodwin, Amy K.; Weerts, Elise M.; Brown, P. Rand; Murphy, Tonya C.; Picklo, Mathew J.; Jakobs, Cornelius; Gibson, K. Michael

doi:10.1016/j.metabol.2005.09.009

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Volume 55, Issue 3 , Pages 353-358, March 2006

Metabolism of γ-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase

Preliminary data were presented at the 41st Annual Meeting of the Society for the Study of Inborn Errors of Metabolism, Amsterdam, the Netherlands, 2004.

Eduard A. Struys
- Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Nanda M. Verhoeven
- Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Erwin E.W. Jansen
- Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Herman J. ten Brink
- Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
Maneesh Gupta
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
Terry G. Burlingame
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
Lawrence S. Quang
- Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA
Timothy Maher
- Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA
Piero Rinaldo
- Biochemical Genetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN, USA
O. Carter Snead
- Division of Neurology and The Program in Brain and Behavior, Department of Pediatrics, Faculty of Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
Amy K. Goodwin
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Elise M. Weerts
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
P. Rand Brown
- Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Tonya C. Murphy
- Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
Mathew J. Picklo
- Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
Cornelius Jakobs
- Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
K. Michael Gibson
- Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA
- Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Pittsburgh School of Medicine and Children's Hospital, Pittsburgh, PA 15213, USA
- Corresponding author. Division of Medical Genetics, Departments of Pediatrics and Pathology, University of Pittsburgh School of Medicine, Rangos Research Center, Pittsburgh, PA 15213, USA. Tel.: +1 412 692 7608; fax: +1 412 692 7816.

Received 9 April 2005; accepted 19 September 2005.

Abstract

γ-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 β-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 (IC₅₀ = 38 μmol/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.