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Partial beta‐oxidation of gamma‐hydroxybutyrate (GHB) in perfused rat livers

GHB is both a brain metabolite and a drug of abuse (date rape drug). We conducted a metabolomic study of GHB metabolism liver, using GC‐MS, GC‐combustion‐IRMS, and LC‐MS‐MS. Rat livers were perfused with recirculating albuminated buffer containing 4 mM glucose and 2 mM of either unlabeled GHB, [U‐13C4]GHB, or [2H6]GHB. In the perfusate, we identified by GC‐MS 2,4‐dihydroxybutyrate, 3,4‐dihydroxybutyrate, and 3‐hydroxypropionate. The mass isotopomer distribution of these compounds in livers perfused with GHB, [U‐13C4]GHB, or [2H6]GHB confirms that they are derived from the partial β‐oxidation of GHB. 3‐Hydroxypropionate may derive from the omega‐oxidation of 3,4‐dihydroxybutyrate (or its CoA ester). GC‐combustion‐IRMS detected 5 unknown metabolites of [U‐13C4]GHB (to be identified). In livers perfused with [U‐13C4]GHB, acetyl‐CoA was unlabeled (even in the absence of glucose), confirming the incomplete βoxidation of GHB. Citric acid cycle intermediates were labeled from [U‐13C4]GHB consistent with entry into the cycle via succinate. LC‐MS‐MS of liver acyl‐CoAs detected an unknown compound (m/z 934 with CoA signature daughter ion at m/z 428). This compound, which becomes M4 with [U‐13C4]GHB, and M6 with [2H6]GHB, contains the 4 C and the 6 H of GHB. In livers perfused with unlabeled GHB and either [U‐13C6]glucose or [1,2‐13C3]acetate, the CoA ester was not labeled. Based on the above and on its rapid migration on the reverse phase LC column, the unknown CoA ester was tentatively identified as 4‐phospho‐GHB‐CoA.