Regulation of P450-derived epoxy fatty acids in cardiovascular diseases

The cytochrome P450 (P450 or CYP) superfamily, while extensively recognized for xenobiotic metabolism, is also critically involved in the biosynthesis of lipid mediators from polyunsaturated fatty acids (PUFAs). Distinct from cyclooxygenase (COX) and lipoxygenase (LOX) pathways, P450 enzymes uniquely catalyze the metabolism of PUFAs such as arachidonic acid (AA), to epoxy fatty acids (EpFAs), such as epoxyeicosatrienoic acids (EETs) and mid-chain or ω-terminal hydroxyeicosatrienoic acids (HETEs). Eicosanoid biosynthesis is initiated by phospholipase A₂ (PLA₂)-mediated release of PUFAs from cellular membranes. Members of the CYP1-CYP4 subfamilies, including prominent human isoforms like CYP2C8, CYP2C9, and CYP2J2, exhibit significant epoxygenase activity, yielding regio- and stereo-specific EETs. These P450-derived oxylipins exert diverse physiological effects, influencing critical processes such as vascular tone, inflammation, angiogenesis, and ischemia-reperfusion injury. Their biological actions are often modulated by soluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH), which hydrolyze EETs to less active dihydroxyeicosatrienoic acids (DHETs). Furthermore, P450s metabolize other PUFAs, including linoleic acid (LA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), generating distinct EpFAs with varying biological effects. Understanding the complex interplay of P450 isoforms, their substrate preferences, and the subsequent metabolic fates of their products is crucial for elucidating their functional roles in health and disease.