CYP2J2 - regulation, function and polymorphism

Polyunsaturated fatty acids (PUFAs) undergo cytochrome P450 (CYP)-dependent oxidation to epoxides that modulate important physiological functions, including vasoactivity, inflammation, nociception, proliferation and viability. One of the most important human CYP epoxygenases is human CYP2J2 that is widely expressed in tissues, especially heart, vascular smooth muscle, salivary glands and placenta. Recent studies have shown that overexpression of CYP2J2 in vivo reverses several pathological processes in animals, including hypertension and other cardiovascular pathologies and insulin resistance. Information on the molecular regulation of CYP2J2 is sparse but supports roles for specificity protein-1 (Sp1) and activator protein-1 (AP-1) in transcription and the micro-RNA Let-7b in post-transcriptional regulation. Exposure to stress stimuli, including pro- and antioxidant factors and pro-inflammatory cytokines regulates CYP2J2, possibly in a cell-specific fashion. CYP2J2 is also subject to genetic variation and the promoter region SNP (CYP2J2-76G > T; *7 allele) reportedly decreases epoxygenase activity in vivo. Several studies have suggested that carriers of the *7 allele may be predisposed to adverse cardiovascular and related health outcomes, although other studies report different findings. Greater understanding of the mechanisms by which CYP2J2 is regulated could provide insights into important pathogenic processes in complex disease states. Such studies may also lead to the development of novel therapeutic strategies that seek to activate CYP2J2 expression in tissues. Additionally, the development of agents that promote fatty acid epoxide production, or stable analogs that retain the activities of the epoxides, offer promising new avenues for utilizing the beneficial actions of these molecules.