Metabolism of gamma-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase.
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.
Struys
Eduard A
EA
Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
Verhoeven
Nanda M
NM
Jansen
Erwin E W
EE
Ten Brink
Herman J
HJ
Gupta
Maneesh
M
Burlingame
Terry G
TG
Quang
Lawrence S
LS
Maher
Timothy
T
Rinaldo
Piero
P
Snead
O Carter
OC
Goodwin
Amy K
AK
Weerts
Elise M
EM
Brown
P Rand
PR
Murphy
Tonya C
TC
Picklo
Mathew J
MJ
Jakobs
Cornelius
C
Gibson
K Michael
KM
D000429:Alcohol Oxidoreductases; D000818:Animals; D005977:Glutarates / Q000032:analysis / Q000378:metabolism*; D007700:Kinetics; D008322:Mammals; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D010215:Papio; D012978:Sodium Oxybate / Q000378:metabolism*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency
D005977:Glutarates; D024101:Mitochondrial Proteins; C019417:alpha-hydroxyglutarate; D012978:Sodium Oxybate; D000429:Alcohol Oxidoreductases; C072878:hydroxyacid-oxoacid transhydrogenase; D050644:Succinate-Semialdehyde Dehydrogenase