Calcium Levulinate: Dietary Supplement and Pro‐drug of Abuse

Abstract

The goal of the study was to investigate the metabolism of levulinate (4‐ketopentanoate, LEV) which as a calcium salt, is used as an oral or intravenous source of calcium. We hypothesized that (i) levulinate is converted to gamma‐hydroxypentanoate (GHP), a new drug of abuse, analog of gamma‐hydroxybutyrate, and (ii) the formation of GHP from LEV is enhanced by ethanol. We investigated the metabolism of LEV and GHP in perfused rat livers and live rats. In both models, LEV was converted to GHP, and GHP was converted to LEV. This interconversion involves a cytosolic NADP‐dehydrogenase. Ethanol decreases the uptake of LEV and increases the formation of GHP from LEV, without affecting the [GHP]/[LEV] ratio. Thus, ethanol appears to inhibit both LEV and GHP catabolism, presumably at the level of 3‐hydroxyacyl‐CoA dehydrogenase. In livers perfused with LEV there was substantial accumulation of LEV‐CoA, GHP‐CoA and 4‐phospho‐GHP‐CoA. In parallel, the concentrations of acetyl‐CoA, malonyl‐CoA, HMG‐CoA methylmalonyl‐CoA and succinyl‐CoA markedly decreased. Thus, the metabolism of LEV and GHP result in substantial CoA trapping which can affect a number of processes. The conversion of LEV to GHP, a drug of abuse, and the stimulation of GHP formation by ethanol is a public health concern since calcium‐LEV is freely available. Supported by NIDDK RoadMap and by NIEHS.