Epoxy-
fatty acids (EpFAs) are endogenous
lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure,
inflammation, angiogenesis, and pain perception. For the past 20 years, soluble
epoxide hydrolase (sEH) has been recognized as the primary
enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug
therapeutics for various diseases including
neuropathic pain. Recent findings suggest that other
epoxide hydrolases (EHs) such as
microsomal epoxide hydrolase (mEH) and
epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human
tissue extracts: hydrolysis of
14,15-EET and 13,14-EDP using selective inhibitors and
protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs.