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 Citations (Scopus)

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

Fingerprint

Detoxification
Metabolism
Epoxide Hydrolases
Metabolites
Toxicity
Carboxylic Acids
Esters
Essential Fatty Acids
Acids
leukotoxin
methyl linoleate
Poisons
Epoxy Compounds
Adult Respiratory Distress Syndrome
Eukaryotic Cells
Linoleic Acid
Esterases
Metabolic Networks and Pathways
Glutathione

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

Metabolism of monoepoxides of methyl linoleate : Bioactivation and detoxification. / Greene, Jessica F.; Williamson, Kristin C.; Newman, John W.; Morisseau, Christophe; Hammock, Bruce D.

In: Archives of Biochemistry and Biophysics, Vol. 376, No. 2, 15.04.2000, p. 420-432.

Research output: Contribution to journalArticle

Greene, JF, Williamson, KC, Newman, JW, Morisseau, C & Hammock, BD 2000, 'Metabolism of monoepoxides of methyl linoleate: Bioactivation and detoxification', Archives of Biochemistry and Biophysics, vol. 376, no. 2, pp. 420-432. https://doi.org/10.1006/abbi.2000.1753
Greene, Jessica F. ; Williamson, Kristin C. ; Newman, John W. ; Morisseau, Christophe ; Hammock, Bruce D. / Metabolism of monoepoxides of methyl linoleate : Bioactivation and detoxification. In: Archives of Biochemistry and Biophysics. 2000 ; Vol. 376, No. 2. pp. 420-432.
@article{4cffa62580354591accb0cdf3c7a831a,
title = "Metabolism of monoepoxides of methyl linoleate: Bioactivation and detoxification",
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.",
keywords = "Esterase, Fatty acids, Glutathione, Leukotoxin, Leukotoxin diol, Linoleic acid, Phospholipids, Soluble epoxide hydrolase",
author = "Greene, {Jessica F.} and Williamson, {Kristin C.} and Newman, {John W.} and Christophe Morisseau and Hammock, {Bruce D.}",
year = "2000",
month = "4",
day = "15",
doi = "10.1006/abbi.2000.1753",
language = "English (US)",
volume = "376",
pages = "420--432",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Metabolism of monoepoxides of methyl linoleate

T2 - Bioactivation and detoxification

AU - Greene, Jessica F.

AU - Williamson, Kristin C.

AU - Newman, John W.

AU - Morisseau, Christophe

AU - Hammock, Bruce D.

PY - 2000/4/15

Y1 - 2000/4/15

N2 - 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.

AB - 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.

KW - Esterase

KW - Fatty acids

KW - Glutathione

KW - Leukotoxin

KW - Leukotoxin diol

KW - Linoleic acid

KW - Phospholipids

KW - Soluble epoxide hydrolase

UR - http://www.scopus.com/inward/record.url?scp=0034656339&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034656339&partnerID=8YFLogxK

U2 - 10.1006/abbi.2000.1753

DO - 10.1006/abbi.2000.1753

M3 - Article

C2 - 10775430

AN - SCOPUS:0034656339

VL - 376

SP - 420

EP - 432

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

IS - 2

ER -