Bioactivation of leukotoxins to their toxic diols by epoxide hydrolase

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.

Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst

“…A 20 μM concentration did not produce a similar inhibitory effect (figure 3). Given previous work suggesting that 9(10)-/12(13)-EpOME represents a protoxin of its epoxide hydrolase metabolite, 9,10-/12,13-DiHOME, in at least some systems (Moghaddam et al 1997), we also examined whether methyl 9(10)-/12(13)-EpOME inhibits the neutrophil respiratory burst. Unlike methyl 9,10-/12,13-DiHOME, inhibition of the respiratory burst was not observed with methyl 9(10)-/12(13)-EpOME, nor with the parent ester, methyl linoleate (figure 3).…”

“…Several studies suggest that the active entities which mediate EpOME-associated toxicity are not the EpOMEs, but their soluble epoxide hydrolase (sEH) metabolites, (±)9,10-dihydroxy-12Z-and (±)12,13-dihydroxy-9Z-octadecenoic acid (9,10-and 12,13-DiHOME, respectively) (Moghaddam et al 1997;Zheng et al 2001). DiHOMEs are detected in human urine under normal conditions (Zurek et al 2002;Newman et al 2002).…”

Epoxide hydrolases: biochemistry and molecular biology

“…Recently, sEH was shown to bioactivate leukotoxin (Fig. 1), a linoleic acid metabolite [57]. These latter substances represent endogenous metabolic products of fatty acid metabolism and implicate a potentially important role for sEH in mediating pathophysiologic and physiologic processes.…”

“…Leukotoxin is bioactivated via sEH metabolism [57]. Leukotoxin is an oxidative metabolite of linoleic acid in leukocytes, that has been associated with multiple organ failure and adult respiratory distress syndrome seen in some severe burn patients.…”

Identification of two epoxide hydrolases in Caenorhabditis elegans that metabolize mammalian lipid signaling molecules

“…Also, in some cases the diols may be biologically active. [9] The epoxyeicosatrienoic acids (EETs) are epoxide-containing compounds produced by the metabolism of arachidonic acid by cytochrome p450 oxygenases. [10] The EETs have anti-inflammatory, as well as vasoconstrictive or vasodilatory properties, depending on the physiological context.…”