Effect of cytochrome P450 polymorphism on arachidonic acid metabolism and their impact on cardiovascular diseases.
Cardiovascular diseases (CVDs) remain the leading cause of death in the developed countries. Taking into account the mounting evidence about the role of cytochrome P450 (CYP) enzymes in cardiovascular physiology, CYP polymorphisms can be considered one of the major determinants of individual susceptibility to CVDs. One of the important physiological roles of CYP enzymes is the metabolism of arachidonic acid. CYP epoxygenases such as CYP1A2, CYP2C, and CYP2J2 metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) which generally possess vasodilating, anti-inflammatory, anti-apoptotic, anti-thrombotic, natriuretic, and cardioprotective effects. Therefore, genetic polymorphisms causing lower activity of these enzymes are generally associated with an increased risk of several CVDs such as hypertension and coronary artery disease. EETs are further metabolized by soluble epoxide hydrolase (sEH) to the less biologically active dihydroxyeicosatrienoic acids (DHETs). Therefore, sEH polymorphism has also been shown to affect arachidonic acid metabolism and to be associated with CVDs. On the other hand, CYP omega-hydroxylases such as CYP4A11 and CYP4F2 metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) which has both vasoconstricting and natriuretic effects. Genetic polymorphisms causing lower activity of these enzymes are generally associated with higher risk of hypertension. Nevertheless, some studies have denied the association between polymorphisms in the arachidonic acid pathway and CVDs. Therefore, more research is needed to confirm this association and to better understand the pathophysiologic mechanisms behind it.
Zordoky
Beshay N M
BN
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
El-Kadi
Ayman O S
AO
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D011110:Polymorphism, Genetic; D044469:Racial Groups / Q000235:genetics
D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases