Epoxyeicosatrienoic Acids: Biosynthesis, Regulation and Actions

Arachidonic acid is a polyunsaturated fatty acid that is esterified at the sn -2 position of the glycerol backbone of membrane phospholipids. Hormonal and paracrine stimuli can activate phospholipases that cleave arachidonic acid from membrane phospholipids. The free intracellular arachidonic acid is then available for metabolism via either the cyclooxygenase, lipoxygenase, or cytochrome P450 monooxygenase pathway. The biological importance of cyclooxygenase and lipoxygenase metabolites of arachidonic acid has been clearly established. In recent years studies have focused on the biological regulation and actions of arachidonic acid metabolites of the cytochrome P450 enzymes. Mammalian cytochrome P450 monooxygenase enzymes catalyze three types of chemical reactions; the hydroxylation of fatty acid carbons near the methyl terminus generating hydroxyeicosatetraenoic acids (HETEs), allylic oxidation generating regioisomeric HETEs, and olefin bond epoxidation to generate regioisomeric epoxyeicosatrienoic acids (EETs; Fig. 1 ). Once formed the cytochrome P450 metabolites possess a wide array of potent biological actions that are not well understood. This chapter will focus on the localization and array of cytochrome P450 enzymes that generate EETs, the regulation of cytochrome P450 enzymes and EETs formation, and the biological actions of EETs.   Fig. 1.  Arachidonic acid metabolic pathways for mammalian cytochrome P450 monooxygenase enzymes.