Metabolism of monoepoxides of methyl linoleate: Bioactivation and detoxification

Jessica F. Greene, Kristin C. Williamson, John W. Newman, Christophe Morisseau, Bruce D. Hammock

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Leukotoxin (ltx) and isoleukotoxin (iltx) methyl esters, are metabolites of methyl linoleic acid, an essential fatty acid. They have been associated with acute respiratory distress syndrome. The observed toxicity of ltx and iltx is, in fact, due to the metabolism of the epoxides to their corresponding diols by soluble epoxide hydrolase (sEH). Herein, we demonstrate that ltx/iltx are toxic in a time-dependent manner to human sEH expressing cells with a LT50 of 10.6 ± 0.8 h and that ltx and iltx have K(M) of 6.15 ± 1.0 and 5.17 ± 0.56 μM, respectively, and V(max) of 2.67 ± 0.04 and 1.86 ± 0.06 μmol/min/mg, respectively, which can be inhibited by sEH inhibitors. We show that four major metabolites of ltx/iltx are formed in our system, including ltx/iltx free acid, ltxd/iltxd, free acid, and phosphotidylcholine and phosphotidylethanolamine containing the carboxylic acid forms of both ltx/iltx and ltxd/iltxd, but that the only metabolite associated with toxicity is the carboxylic acid form of ltxd/iltxd, suggesting the involvement of cellular esterases. We demonstrate that a serine esterase inhibitor provides some protection from the toxicity of epoxy fatty esters to sEH expressing cells as do intercellular free sulfhydryls, but that this protection is not due to glutathione conjugation. With these data, we have proposed an extension of the metabolic pathway for ltx/iltx in eukaryotic cells. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)420-432
Number of pages13
JournalArchives of Biochemistry and Biophysics
Volume376
Issue number2
DOIs
StatePublished - Apr 15 2000

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Keywords

  • Esterase
  • Fatty acids
  • Glutathione
  • Leukotoxin
  • Leukotoxin diol
  • Linoleic acid
  • Phospholipids
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Greene, J. F., Williamson, K. C., Newman, J. W., Morisseau, C., & Hammock, B. D. (2000). Metabolism of monoepoxides of methyl linoleate: Bioactivation and detoxification. Archives of Biochemistry and Biophysics, 376(2), 420-432. https://doi.org/10.1006/abbi.2000.1753