title: Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8.
abstract: Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs.
authors.affiliation: Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy.
authors.forename: Asuna
authors.initials: A
authors.lastname: Senda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mukai
authors.forename: Takaki
authors.initials: T
authors.lastname: Toda
authors.forename: Toru
authors.initials: T
authors.lastname: Hayakawa
authors.forename: Miki
authors.initials: M
authors.lastname: Yamashita
authors.forename: Erik
authors.initials: E
authors.lastname: Eliasson
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Nobuo
authors.initials: N
authors.lastname: Inotsume
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D065727:Cytochrome P-450 CYP2C8 / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism*
chemical_list: D057911:Angiotensin Receptor Antagonists; D002317:Cardiovascular Agents; D015777:Eicosanoids; D011945:Receptors, Angiotensin; D016718:Arachidonic Acid; D065727:Cytochrome P-450 CYP2C8