Stiftung Tierärztliche Hochschule Hannover (TiHo)

Dietary polyphenols inhibit the cytochrome P450 monooxygenase branch of the arachidonic acid cascade with remarkable structure-dependent selectivity and potency

Kampschulte, Nadja; Alasmer, Ayah; Empl, Michael T ORCID; Krohn, Michael; Steinberg, Pablo GND; Schebb, Nils Helge ORCID

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 ω-hydroxylating CYP4F2 and CYP4A11 were investigated, as well as the epoxidizing CYP2C-subfamily and CYP3A4 along with the (ω-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, ω-hydroxylation, and (ω-n)-hydroxylation of AA with IC50 values of 4.4-9.8, 2.9-10, and 10-25 μM, respectively. Other flavones such as wogonin selectively inhibited CYP1A1-catalyzed (ω-n)-hydroxylation with an IC50 value of 0.10-0.22 μM, while the isoflavone genistein was a selective ω-hydroxylase inhibitor (IC50: 5.5-46 μM). 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 (Papp: 4.5 ± 1 × 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 μM) 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.

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