Action of epoxyeicosatrienoic acids on cellular function

Abstract

Epoxyeicosatrienoic acids (EETs), which function primarily as autocrine and paracrine mediators in the cardiovascular and renal systems, are synthesized from arachidonic acid by cytochrome P-450 epoxygenases. They activate smooth muscle large-conductance Ca2+-activated K+ channels, producing hyperpolarization and vasorelaxation. EETs also have anti-inflammatory effects in the vasculature and kidney, stimulate angiogenesis, and have mitogenic effects in the kidney. Many of the functional effects of EETs occur through activation of signal transduction pathways and modulation of gene expression, events probably initiated by binding to a putative cell surface EET receptor. However, EETs are rapidly taken up by cells and are incorporated into and released from phospholipids, suggesting that some functional effects may occur through a direct interaction between the EET and an intracellular effector system. In this regard, EETs and several of their metabolites activate peroxisome proliferator-activated receptor α (PPARα) and PPARγ, suggesting that some functional effects may result from PPAR activation. EETs are metabolized primarily by conversion to dihydroxyeicosatrienoic acids (DHETs), a reaction catalyzed by soluble epoxide hydrolase (sEH). Many potentially beneficial actions of EETs are attenuated upon conversion to DHETs, which do not appear to be essential under routine conditions. Therefore, sEH is considered a potential therapeutic target for enhancing the beneficial functions of EETs.

Mitochondrial P450-dependent arachidonic acid metabolism by TCDD-induced hepatic CYP1A5; conversion of EETs to DHETs by mitochondrial soluble epoxide hydrolase

“…The chick sEH was recognized by an antibody to mouse sEH, and the rank order for conversion of EETs to DHETs by CE liver sEH observed in these experiments was the same as reported for the mammalian enzyme: 14,15-EET > 11,12-EET = 8,9-EET, with negligible conversion of 5,6-EET [16]. The findings are consistent with conservation of structure and function of this enzyme among species.…”

“…Effects of EETs on liver cells or liver microsomes include increased intracellular Ca 2+ , vasopressin stimulated glycogenolysis, activation of phosphorylase and ADP ribosylation (reviewed in Spector and Norris [16]). Moreover, putative targets for cardiovascular actions of EETs (i.e K ATP and BK Ca channels, and signaling pathways regulating inflammatory responses, angiogenesis and cell cycling (via mitogen activated protein kinase (MAPK), Akt and Src-dependent pathways)) are present and active in liver [44,45].…”

“…The P450 aa products include four regioisomeric aa epoxides (5,6-8,9-11,12-14,15-epoxyeicosatrienoic acids, EETs), each with 2 stereoisomers, mid-chain mono-hydroxylated products (HETEs) and monohydroxylated ω terminal alcohols (including 18-, 19-and 20-HETE) [14]. EETs can be converted to vicdihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (EPHX2, sEH) or microsomal epoxide hydrolase (EPHX1) [15,16]. TCDD-induced CYP1A5 [10] and human CYP1A2 [17,18] generate mainly EETs as do some constitutive P450 aa epoxygenases (i.e.…”

“…TCDD-induced CYP1A5 [10] and human CYP1A2 [17,18] generate mainly EETs as do some constitutive P450 aa epoxygenases (i.e. CYPs 2B, 2C and 2J) [1,16,19], while P450s in the CYP4 family are responsible for 20-HETE formation [19,20]. P450 aa metabolites are biologically active compounds, whose effects have been most extensively investigated and recognized with respect to the cardiovascular system.…”

“…P450 aa metabolites are biologically active compounds, whose effects have been most extensively investigated and recognized with respect to the cardiovascular system. EETs are considered to be generally vasodilatory and to provide protection in cardiac ischemiareperfusion injury, while 20-HETE is considered to be mainly vasoconstrictive and to have a possible role in hypertension [16,19]. The role of P450 aa metabolites in liver physiology and pathophysiology is not yet understood [21].…”