Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase

Mehran F. Moghaddam, David F. Grant, Jeffrey M. Cheek, Jessica F. Greene, Kristin C. Williamson, Bruce D. Hammock

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

Leukotoxin is a linoleic acic oxide produced by leukocytes and has been associated with the multiple organ failure and adult respiratory distress syndrome seen in some severe burn patients. Leukotoxin has been reported to be toxic when injected into animals intravenously. Herein, we report that this lipid is not directly cytotoxic in at least two in vitro systems. Using a baculovirus expression system we demonstrate that leukotoxin is only cytotoxic in the presence of epoxide hydrolases. In addition, it is the diol metabolite that proves toxic to pulmonary alveolar epithelial cells, suggesting a critical role for the diol in leukotoxin-associated respiratory disease. In vivo data also support the toxicity of leukotoxin diol. For the first time we demonstrate that soluble epoxide hydrolase can bioactivate epoxides to diols that are apparently cytotoxic. Thus leukotoxin should be regarded as a protoxin corresponding to the more toxic diol. This clearly has implications for designing new clinical interventions.

Original languageEnglish (US)
Pages (from-to)562-566
Number of pages5
JournalNature Medicine
Volume3
Issue number5
StatePublished - 1997

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Epoxide Hydrolases
Poisons
Alveolar Epithelial Cells
Multiple Organ Failure
Acyclovir
Baculoviridae
Epoxy Compounds
Adult Respiratory Distress Syndrome
Pulmonary diseases
Oxides
Metabolites
Leukocytes
Toxicity
Lipids
Animals
Lung
leukotoxin
9,10-dihydroxy-12-octadecenoic acid

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Moghaddam, M. F., Grant, D. F., Cheek, J. M., Greene, J. F., Williamson, K. C., & Hammock, B. D. (1997). Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase. Nature Medicine, 3(5), 562-566.

Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase. / Moghaddam, Mehran F.; Grant, David F.; Cheek, Jeffrey M.; Greene, Jessica F.; Williamson, Kristin C.; Hammock, Bruce D.

In: Nature Medicine, Vol. 3, No. 5, 1997, p. 562-566.

Research output: Contribution to journalArticle

Moghaddam, MF, Grant, DF, Cheek, JM, Greene, JF, Williamson, KC & Hammock, BD 1997, 'Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase', Nature Medicine, vol. 3, no. 5, pp. 562-566.
Moghaddam MF, Grant DF, Cheek JM, Greene JF, Williamson KC, Hammock BD. Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase. Nature Medicine. 1997;3(5):562-566.
Moghaddam, Mehran F. ; Grant, David F. ; Cheek, Jeffrey M. ; Greene, Jessica F. ; Williamson, Kristin C. ; Hammock, Bruce D. / Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase. In: Nature Medicine. 1997 ; Vol. 3, No. 5. pp. 562-566.
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