Toxicity of epoxy fatty acids and related compounds to cells expressing human soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) is suggested to alter the mode of action an d increase the toxic potency of fatty acid epoxides. To characterize the st ructural features necessary for sEH-dependent epoxy fatty acid toxicity, 75 aliphatic compounds were assayed for cytotoxicity in the presence and abse nce of sEH. Three groups of aliphatic epoxide-diol pairs were described by their observed differential toxicity. Group I compounds were typified by te rminal epoxides whose toxicity was reduced in the presence of sEH. Group II compounds were toxic in either their epoxide or diol form, but toxicity wa s unaffected by sEH. Group III compounds exhibited sEH-dependent toxicity a nd were therefore used to investigate the structural elements required for cytotoxicity in this study. The optimal structure for group III compounds a ppeared to be a fatty acid 18-20 atoms long (e.g., a carbon backbone plus a terminal heteroatom) with an epoxide positioned between C-7 and C-12. In t he absence of sEH, replacement of epoxides with a vicinal diol was required for toxicity. While diol stereochemistry was unimportant, vicinal diol-ind uced toxicity exhibited fewer positional constraints to toxicity than sEH-d ependent epoxide toxicity. Tested fatty acids and esters with neither an ep oxide nor a vicinal diol were not toxic. These data support the hypothesis that long-chain epoxy fatty acid methyl esters are potential pro-toxins met abolized by sEH to more toxic diols. Furthermore, our results suggest that the endogenous compounds, leukotoxin methyl ester, 9,10(Z)-epoxyoctadec-9(Z )-enoic acid methyl ester, and isoleukotoxin methyl ester, 12,13(Z)-epoxyoc tadec-9(Z)-enoic acid methyl ester, are structurally optimized to elicit th e observed effect.