The role of methyl-linoleic acid epoxide and diol metabolites in the amplified toxicity of linoleic acid and polychlorinated biphenyls to vascular endothelial cells

Selected dietary lipids may increase the atherogenic effects of environment al chemicals, such as polychlorinated biphenyls (PCBs), by cross-amplifying mechanisms leading to dysfunction of the vascular endothelium. We have sho wn previously that the (omega -6 parent fatty acid, linoleic acid, or 3,3 ' ,4,4 ' -tetrachlorobiphenyl (PCB 77), an aryl hydrocarbon (Ah) receptor ag onist, independently can cause disruption of endothelial barrier function. Furthermore, cellular enrichment with linoleic acid can amplify PCB-induced endothelial cell dysfunction. We hypothesize that the amplified toxicity o f linoleic acid and PCBs to endothelial cells could be mediated in part by cytotoxic epoxide metabolites of linoleic acid called leukotoxins (LTX) or their diol derivatives (LTXD). Exposure to LTXD resulted in a dose-dependen t increase in albumin transfer across endothelial cell monolayers, whereas this disruption of endothelial barrier function was observed only at a high concentration of LTX. Pretreatment with the cytosolic epoxide hydrolase in hibitor 1-cyclohexyl-3-dodecyl urea partially protected against the observe d LTX-induced endothelial dysfunction. Endothelial cell activation mediated by LTX and/or LTXD also enhanced nuclear translocation of the transcriptio n factor NF-KB and gene expression of the inflammatory cytokine IL-6. Inhib iting cytosolic epoxide hydrolase decreased the LTX-mediated induction of b oth NF-KB and the IL-6 gene, whereas the antioxidant vitamin E did not bloc k LTX-induced endothelial cell activation. Most importantly, inhibition of cytosolic epoxide hydrolase blocked both linoleic acid-induced cytotoxicity , as well as the additive toxicity of linoleic acid plus PCB 77 to endothel ial cells. Interestingly, cellular uptake and accumulation of linoleic acid was markedly enhanced in the presence of PCB 77. These data suggest that c ytotoxic epoxide metabolites of linoleic acid play a critical role in linol eic acid-induced endothelial cell dysfunction. Furthermore, the severe toxi city of PCBs in the presence of linoleic acid may be due in part to the gen eration of epoxide and diol metabolites. These findings have implications i n understanding interactive mechanisms of how dietary fats can modulate dys function of the vascular endothelium mediated by certain environmental cont aminants. (C) 2001 Academic Press.