Arachidonic acid epoxygenase pathway

The Arachidonic acid epoxygenase pathway is a major metabolic branch of the arachidonic acid cascade, functioning alongside the cyclooxygenase (COX) and lipoxygenase (LOX) pathways [1, 13]. Primarily mediated by Cytochrome P450 (CYP) enzymes, particularly the CYP2C and CYP2J subfamilies, this pathway converts arachidonic acid into four regioisomeric epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EET [2, 3]. These EETs function as potent autocrine and paracrine signaling molecules that regulate vascular tone, inflammation, and cellular survival [2, 11]. They are known for their vasodilatory, anti-inflammatory, and cardioprotective effects, often acting through the activation of large-conductance calcium-activated potassium (BKCa) channels [3, 8]. Therapeutically, the pathway is targeted primarily by inhibiting the enzyme soluble epoxide hydrolase (sEH), which is responsible for the rapid degradation of EETs into less active dihydroxyeicosatrienoic acids (DHETs) [1, 10]. By stabilizing EET levels, sEH inhibitors offer a promising approach for treating hypertension, heart failure, chronic pain, and inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and diabetic nephropathy [10, 14, 15]. However, because EETs can also promote angiogenesis and cell proliferation, there are concerns that modulating this pathway might inadvertently facilitate tumor progression in certain cancers [4, 15]. Current research continues to explore the balance between the protective cardiovascular effects of the pathway and its potential roles in metabolic and neurodegenerative diseases [7, 12].

Other names

Cytochrome P450 epoxygenase pathwayCYP epoxygenase pathwayAA-CYP-EET pathwayThird pathway of arachidonic acid metabolismEpoxygenase pathway of arachidonic acid metabolism

The primary therapeutic mechanism is the inhibition of soluble epoxide hydrolase (sEH) to stabilize and increase the levels of bioactive epoxyeicosatrienoic acids (EETs). Alternatively, the pathway can be targeted via direct inhibition of CYP epoxygenases (e.g., CYP2J2) to reduce EET levels in conditions like cancer, or through the use of synthetic EET analogs/mimetics to activate downstream protective signaling pathways.