Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

• PUFA are oxidized to PUFA epoxides by cytochrome P450 epoxygenases.
• PUFA epoxides function as mediators in the cardiovascular, renal and nervous system.
• PUFA epoxides activate receptor-mediated signaling pathways and ion channels.
• Soluble epoxide hydrolase inactivates PUFA epoxides by hydrolysis to PUFA diols.
• Inhibition of soluble epoxide hydrolase potentiates the action of PUFA epoxides.

Polyunsaturated fatty acids (PUFA) are oxidized by cytochrome P450 epoxygenases to PUFA epoxides which function as potent lipid mediators. The major metabolic pathways of PUFA epoxides are incorporation into phospholipids and hydrolysis to the corresponding PUFA diols by soluble epoxide hydrolase. Inhibitors of soluble epoxide hydrolase stabilize PUFA epoxides and potentiate their functional effects. The epoxyeicosatrienoic acids (EETs) synthesized from arachidonic acid produce vasodilation, stimulate angiogenesis, have anti-inflammatory actions, and protect the heart against ischemia–reperfusion injury. EETs produce these functional effects by activating receptor-mediated signaling pathways and ion channels. The epoxyeicosatetraenoic acids synthesized from eicosapentaenoic acid and epoxydocosapentaenoic acids synthesized from docosahexaenoic acid are potent inhibitors of cardiac arrhythmias. Epoxydocosapentaenoic acids also inhibit angiogenesis, decrease inflammatory and neuropathic pain, and reduce tumor metastasis. These findings indicate that a number of the beneficial functions of PUFA may be due to their conversion to PUFA epoxides. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.