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Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate.

Publication ,  Journal Article
Harris, SR; Zhang, G-F; Sadhukhan, S; Murphy, AM; Tomcik, KA; Vazquez, EJ; Anderson, VE; Tochtrop, GP; Brunengraber, H
Published in: J Biol Chem
February 18, 2011

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.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 18, 2011

Volume

286

Issue

7

Start / End Page

5895 / 5904

Location

United States

Related Subject Headings

  • Substance-Related Disorders
  • Rats, Sprague-Dawley
  • Rats
  • Perfusion
  • Pentanoic Acids
  • Oxidation-Reduction
  • Mitochondria, Liver
  • Male
  • Liver
  • Levulinic Acids
 

Citation

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Harris, S. R., Zhang, G.-F., Sadhukhan, S., Murphy, A. M., Tomcik, K. A., Vazquez, E. J., … Brunengraber, H. (2011). Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate. J Biol Chem, 286(7), 5895–5904. https://doi.org/10.1074/jbc.M110.196808
Harris, Stephanie R., Guo-Fang Zhang, Sushabhan Sadhukhan, Anne M. Murphy, Kristyen A. Tomcik, Edwin J. Vazquez, Vernon E. Anderson, Gregory P. Tochtrop, and Henri Brunengraber. “Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate.J Biol Chem 286, no. 7 (February 18, 2011): 5895–5904. https://doi.org/10.1074/jbc.M110.196808.
Harris SR, Zhang G-F, Sadhukhan S, Murphy AM, Tomcik KA, Vazquez EJ, et al. Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate. J Biol Chem. 2011 Feb 18;286(7):5895–904.
Harris, Stephanie R., et al. “Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate.J Biol Chem, vol. 286, no. 7, Feb. 2011, pp. 5895–904. Pubmed, doi:10.1074/jbc.M110.196808.
Harris SR, Zhang G-F, Sadhukhan S, Murphy AM, Tomcik KA, Vazquez EJ, Anderson VE, Tochtrop GP, Brunengraber H. Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate. J Biol Chem. 2011 Feb 18;286(7):5895–5904.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 18, 2011

Volume

286

Issue

7

Start / End Page

5895 / 5904

Location

United States

Related Subject Headings

  • Substance-Related Disorders
  • Rats, Sprague-Dawley
  • Rats
  • Perfusion
  • Pentanoic Acids
  • Oxidation-Reduction
  • Mitochondria, Liver
  • Male
  • Liver
  • Levulinic Acids