Soluble Epoxide Hydrolase - Clinical Significance

Clinical Significance

Through metabolism of EETs and other lipid mediators, sEH plays a role in several diseases, including hypertension, cardiac hypertrophy, arteriosclerosis, brain and heart ischemia/reperfusion injury, cancer and pain. Because of its possible role in cardiovascular and other diseases, sEH is being pursued as a pharmacological target, and potent small molecule inhibitors are available.

Because of the implications to human health, sEH has been pursued as a pharmaceutical target and several sEH inhibitors have been developed in the private and public sectors. One such inhibitor, UC1153 (AR9281), was taken to a phase IIA clinal trial for treatment of hypertension by Arête Therapeutics. However, UC1153 failed the clinical trial, due in large part because of its poor pharmacokinetic properties. Since this trial, a different sEH inhibitor, GSK2256294, developed for chronic obstructive pulmonary disease by GlaxoSmithKline has entered the pre-recruiting phase of a phase I clinical trial for obese male smokers. Thus, interest continues in sEH as a therapeutic target.

One indication of the possible therapeutic value of sEH inhibition comes from studies examining physiologically relevant single nucleotide polymorphisms (SNPs) of sEH in human populations. The Coronary Artery Risk Development in Young Adults (CARDIA) and the Atherosclerosis Risk in Communities (ARIC) studies both associated SNPs in the sEH coding region with coronary heart disease. In these studies, two nonsynonymous SNPs were identified, R287Q and K55R. R287Q changes the arginine in position 287 in the most frequent allele to glutamine, while K55R changes the lysine in position 55 to an arginine. R287Q was associated with coronary artery calcification in African American population participating in the CARDIA study. The K55R allele is associated with the risk of developing coronary heart disease in Caucasians participating in the ARIC study, where it was also associated with a higher risk of hypertension and ischemic stroke in male homozygotes.