Dietary Polyphenols Inhibit the Cytochrome P450 Monooxygenase Branch of the Arachidonic Acid Cascade with Remarkable Structure-Dependent Selectivity and Potency

The products of the cytochrome P450 monooxygenase (CYP)-catalyzed oxidation of arachidonic acid (AA), that is, epoxy- and hydroxy-fatty acids, play a crucial role in the homeostasis of several physiological processes. In a liver microsome-based multienzyme assay using AA as natural substrate, we investigated how polyphenols inhibit different oxylipin-forming CYP in parallel but independently from each other. The omega-hydroxylating CYP4F2 and CYP4A11 were investigated, as well as the epoxidizing CYP2C-subfamily and CYP3A4 along with the (omega-n)-hydroxylating CYP1A1 and CYP2E1. The oxylipin formation was inhibited by several polyphenols with a remarkable selectivity and a potency comparable to known CYP inhibitors. The flavone apigenin inhibited the epoxidation, omega-hydroxylation, and (omega-n)-hydroxylation of AA with IC50 values of 4.4-9.8, 2.9-10, and 10-25 mu M, respectively. Other flavones such as wogonin selectively inhibited CYP1A1-catalyzed (omega-n)-hydroxylation with an IC50 value of 0.10-0.22 mu M, while the isoflavone genistein was a selective co-hydroxylase inhibitor (IC50: 5.5-46 mu M). Of note, the flavanone naringenin and the anthocyanidin perlargonidin did not inhibit CYPs of the AA cascade. Moderate permeability of apigenin as tested in the Caco-2 model of intestinal absorption (P-app : 4.5 +/- 1 x 10(-6) cm/s) and confirmation of the inhibition of 20-HETE formation by apigenin in the colorectal cancer-derived cell line HCT 116 (IC50: 1.5-8.8 mu M) underline the possible in vivo relevance of these effects. Further research is needed to better understand how polyphenols impact human health by this newly described molecular mode of action.