Evidence for the participation of a cytosolic NADP+-dependent oxidoreductase in the catabolism of gamma-hydroxybutyrate in vivo.
The concentration of gamma-hydroxybutyrate (GHB) in brain, kidney, and muscle as well as the clearance of [1-14C]GHB in plasma have been found to be altered by the administration of a number of metabolic intermediates and drugs that inhibit the NADP+-dependent oxidoreductase, "GHB dehydrogenase," an enzyme that catalyzes the oxidation of GHB to succinic semialdehyde. Administration of valproate, salicylate, and phenylacetate, all inhibitors of GHB dehydrogenase, significantly increased the concentration of GHB in brain; salicylate increased GHB concentration in kidney, and alpha-ketoisocaproate increased GHB levels in kidney and muscle. The half-life of [1-14C]GHB in plasma was decreased by D-glucuronate, a compound that stimulates the oxidation of GHB by this enzyme and was increased by a competitive substrate of the enzyme, L-gulonate. The results of these experiments suggest a role for GHB dehydrogenase in the regulation of tissue levels of endogenous GHB.
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D018756:GABA Antagonists; D005965:Glucuronates / Q000378:metabolism; D006884:Hydroxybutyrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006885:Hydroxybutyrates / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D010648:Phenylacetates / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012978:Sodium Oxybate / Q000378:metabolism*; D012980:Sodium Salicylate / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives
D018756:GABA Antagonists; D005965:Glucuronates; D006885:Hydroxybutyrates; D007651:Keto Acids; D010648:Phenylacetates; D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid; D012978:Sodium Oxybate; C013082:alpha-ketoisocaproic acid; D006884:Hydroxybutyrate Dehydrogenase; C019416:4-hydroxybutyrate dehydrogenase; C009338:succinic semialdehyde; D012980:Sodium Salicylate