Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase

Nat Med. 1997 May;3(5):562-6. doi: 10.1038/nm0597-562.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Baculoviridae
  • Cell Line
  • Cell Membrane Permeability
  • Cells, Cultured
  • Cytotoxins / metabolism
  • Cytotoxins / toxicity*
  • Electric Conductivity
  • Epithelial Cells
  • Epithelium / physiology
  • Epoxide Hydrolases / metabolism*
  • Humans
  • Intercellular Junctions
  • Ion Transport
  • Linoleic Acids / metabolism
  • Linoleic Acids / toxicity*
  • Male
  • Mice
  • Pulmonary Alveoli / cytology
  • Pulmonary Alveoli / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / metabolism
  • Spodoptera


  • Cytotoxins
  • Linoleic Acids
  • Recombinant Proteins
  • 9,10-epoxy-12-octadecenoic acid
  • Epoxide Hydrolases