Stabilization of the cytochrome P450 products by sEHIs during inflammation has unforeseen effects on the AA cascade. The sEHIs not only transcriptionally suppress COX-2 expression in the periphery and the CNS but their use also leads to significant changes in the levels of LOX produced lipid mediators [58]. These changes do not seem to be dominated by laws of mass action where one would expect to see only increased flow of substrate towards other branches when one branch is blocked. Thus a complex cross-talk among the three branches of the AA cascade exists as well as crosstalk among chemokine, cytokine, and other systems. To take advantage of the transcriptional down-regulation of the COX isozymes by sEHIs we employed a two pronged approach. On one hand we tested the effects of co-administration of a sEH inhibitor with the selective COX-2 inhibitor celecoxib and on the other hand we designed and tested a series of dual sEH/COX-2 inhibitors. The resulting dual sEH/COX-2 inhibitor is similarly potent compared to rofecoxib although less potent than celecoxib and has low nM inhibitory potency on recombinant
