Year: 2011
Type: article
Abstract: The calcium salt of levulinate is used as an oral or intravenous source of calcium.We hypothesized that (i) levulinate is converted to 4-hydroxypentanoate, a new drug of abuse, analog of 4-hydroxybutyrate, (ii) the formation of 4-hydroxypentanoate from levulinate is enhanced by ethanol oxidation, and (iii) the metabolism of levulinate results in CoA trapping in levulinate-derived CoA esters.We confirmed these hypotheses in perfused rat livers, live rats, and in liver subcellular preparations, using a combination of metabolomics and mass isotopomer analysis.Levulinate is reduced to (R)-4-hydroxypentanoate by cytosolic and mitochondrial dehydrogenases, which are NADPH-and NADH-dependent, respectively.A mitochondrial dehydrogenase or racemase system also forms (S)-4hydroxypentanoate.We showed that levulinate is catabolized by three pathways to acetyl-CoA, propionyl-CoA, and lactate.Also, levulinate metabolism leads to substantial accumulation of levulinyl-CoA, 4-hydroxypentanoyl-CoA and 4-phosphopentanoyl-CoA (a novel type of CoA ester).Ethanol stimulates (6 fold) the accumulation of 4phosphopentanoyl-CoA, a potential neuromodulator, which might contribute to the brain toxicity of levulinate. xv xviIn live rats given an oral gavage of calcium levulinate ± ethanol, we observed substantial accumulation of levulinate-derived CoA esters (including 4-phosphopentanoyl-CoA) in the brain and liver.These esters remained longer in the brain than in the liver.Lastly, we identified new fates of levulinate metabolism in the liver and brain.First, levulinyl-CoA is elongated with acetyl-CoA to 3,6-diketoheptanoyl-CoA, which is converted to two types of cyclical CoA esters: one with a cyclopentane ring and one with a pyrrole ring.The latter evokes pyrrole compounds formed in the brain by the binding of toxic gamma-diketones (such as 2,5-diketohexane) to the ε-nitrogen of lysine residues of proteins.These cyclical CoA esters were identified in rat livers perfused with levulinate, and in livers and brains from rats gavaged with calcium levulinate ± ethanol.Such compounds may contribute to the toxicity of levulinate.Overall, oral ingestion of calcium levulinate + ethanol is a public health concern since calcium-levulinate is freely available.
Author: Stephanie R. Harris
Institution: Case Western Reserve University
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W2233720256