Stabilized epoxygenated fatty acids regulate inflammation, pain, angiogenesis and cancer

Abstract

Epoxygenated fatty acids (EpFAs), which are lipid mediators produced by cytochrome P450 epoxygenases from polyunsaturated fatty acids, are important signaling molecules known to regulate various biological processes including inflammation, pain and angiogenesis. The EpFAs are further metabolized by soluble epoxide hydrolase (sEH) to form fatty acid diols which are usually less-active. Pharmacological inhibitors of sEH that stabilize endogenous EpFAs are being considered for human clinical uses. Here we review the biology of ω-3 and ω-6 EpFAs on inflammation, pain, angiogenesis and tumorigenesis.

Keywords: Cytochrome P450 epoxygenase; Epoxydocosapentaenoic acids; Epoxyeicosatrienoic acids; Soluble epoxide hydrolase.

Fig. 1

The metabolism of arachidonic acid by cytochrome P450 (CYP) epoxygenases (largely CYP2C and CYP2J) leads to the formation of epoxyeicosatrienoic acids (EETs) including four regioisomers of 5,6-, 8,9-, 11,12- and 14,15-EET. EETs are further metabolized by soluble epoxide hydrolase (sEH) to form the fatty acid diols termed dihydroxyeicosatrienoic acids (DHETs) which are usually less-active or inactive.

Fig. 2

The ω-3 PUFAs including EPA and DHA are highly efficient alternative substrates of the CYP/sEH pathway. The metabolism of EPA and DHA by CYP epoxygenases generates ω-3-series epoxygenated fatty acids (EpFAs), including 5 regioisomers of EEQs from EPA and 6 EDP isomers from DHA. Compared with ARA, EPA and DHA showed higher or similar activities toward the metabolism by CYP epoxygenases. Compared with EETs, EEQs and EDPs are also better substrates of sEH to be metabolized to the corresponding fatty acid diols (DiHETE and DiHDPA respectively) with the exception of 19,20-EDP.

Fig. 3

Genetic deletion or pharmacological inhibition of sEH in ω-6-rich and ω-3-rich tissues leads to accumulation of EETs and EDPs respectively, leading to different effects on angiogenesis.