Angiotensin II Receptor Blockers Inhibit the Generation of Epoxyeicosatrienoic Acid from Arachidonic Acid in Recombinant CYP2C9, CYP2J2 and Human Liver Microsomes

Abstract

Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, have cardioprotective effects including anti-inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2 and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC₅₀ ) of AA metabolism was losartan <telmisartan <irbesartan <candesartan <olmesartan <valsartan via CYP2C9, and telmisartan <irbesartan <olmesartan <losartan <candesartan and valsartan via CYP2J2. The order for the HLMs was losartan <telmisartan <irbesartan <olmesartan <candesartan <valsartan. Some ARBs having lower concentration of IC₅₀ indicate that these ARBs might inhibit the AA metabolism in the liver.