Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate.
Calcium levulinate (4-ketopentanoate) is used as an oral and parenteral source of calcium. We hypothesized that levulinate is converted in the liver to 4-hydroxypentanoate, a new drug of abuse, and that this conversion is accelerated by ethanol oxidation. We confirmed these hypotheses in live rats, perfused rat livers, and liver subcellular preparations. Levulinate is reduced to (R)-4-hydroxypentanoate by a cytosolic and a mitochondrial dehydrogenase, which are NADPH- and NADH-dependent, respectively. A mitochondrial dehydrogenase or racemase system also forms (S)-4-hydroxypentanoate. In livers perfused with [(13)C(5)]levulinate, there was substantial CoA trapping in levulinyl-CoA, 4-hydroxypentanoyl-CoA, and 4-phosphopentanoyl-CoA. This CoA trapping was increased by ethanol, with a 6-fold increase in the concentration of 4-phosphopentanoyl-CoA. Levulinate is catabolized by 3 parallel pathways to propionyl-CoA, acetyl-CoA, and lactate. Most intermediates of the 3 pathways were identified by mass isotopomer analysis and metabolomics. The production of 4-hydroxypentanoate from levulinate and its stimulation by ethanol is a potential public health concern.
Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Stephanie R
SR
Harris
Guo-Fang
GF
Zhang
Sushabhan
S
Sadhukhan
Anne M
AM
Murphy
Kristyen A
KA
Tomcik
Edwin J
EJ
Vazquez
Vernon E
VE
Anderson
Gregory P
GP
Tochtrop
Henri
H
Brunengraber
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003593:Cytoplasm / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D007982:Levulinic Acids / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D010421:Pentanoic Acids / Q000009:adverse effects / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D019966:Substance-Related Disorders
D002492:Central Nervous System Depressants; D004791:Enzyme Inhibitors; D007982:Levulinic Acids; D010421:Pentanoic Acids; D000431:Ethanol; C032246:levulinic acid; D002118:Calcium