Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases

摘要

Cyclooxygenase (COX-1/COX-2)-catalyzed eicosanoid formation plays a key role in inflammation-associated diseases. Natural forms of vitamin E are recently shown to be metabolized to long-chain carboxychromanols and their sulfated counterparts. Here we find that vitamin E forms differentially inhibit COX-2-catalyzed prostaglandin E2 in IL-1β-stimulated A549 cells without affecting COX-2 expression, showing the relative potency of γ-tocotrienol ≈ δ-tocopherol > γ-tocopherol ≫ α- or β-tocopherol. The cellular inhibition is partially diminished by sesamin, which blocks the metabolism of vitamin E, suggesting that their metabolites may be inhibitory. Consistently, conditioned media enriched with long-chain carboxychromanols, but not their sulfated counterparts or vitamin E, reduce COX-2 activity in COX-preinduced cells with 5 μM arachidonic acid as substrate. Under this condition, 9′- or 13′-carboxychromanol, the vitamin E metabolites that contain a chromanol linked with a 9- or 13-carbon-length carboxylated side chain, inhibits COX-2 with an IC50 of 6 or 4 μM, respectively. But 13′-carboxychromanol inhibits purified COX-1 and COX-2 much more potently than shorter side-chain analogs or vitamin E forms by competitively inhibiting their cyclooxygenase activity with Ki of 3.9 and 10.7 μM, respectively, without affecting the peroxidase activity. Computer simulation consistently indicates that 13′-carboxychromanol binds more strongly than 9′-carboxychromanol to the substrate-binding site of COX-1. Therefore, long-chain carboxychromanols, including 13′-carboxychromanol, are novel cyclooxygenase inhibitors, may serve as anti-inflammation and anticancer agents, and may contribute to the beneficial effects of certain forms of vitamin E.