BIOACTIVATION OF LEUKOTOXINS TO THEIR TOXIC DIOLS BY EPOXIDE HYDROLASE

Leukotoxin is a linoleic acic oxide produced by leukocytes and has bee n associated with the multiple organ failure and adult respiratory dis tress 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 hydrolas es. In addition, it is the diol metabolite that proves toxic to pulmon ary alveolar epithelial cells, suggesting a critical role for the diol in leukotoxin-associated respiratory disease, In vivo data also suppo rt 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 prot oxin corresponding to the more toxic diol. This clearly has implicatio ns for designing new clinical interventions.