title: Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases.
abstract: 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 E(2) in IL-1beta-stimulated A549 cells without affecting COX-2 expression, showing the relative potency of gamma-tocotrienol approximately delta-tocopherol > gamma-tocopherol >> alpha- or beta-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 microM 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 IC(50) of 6 or 4 microM, 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 K(i) of 3.9 and 10.7 microM, 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.
authors.affiliation: Department of Foods and Nutrition, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN 47907, USA. qjiang@purdue.edu
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.forename: Xinmin
authors.initials: X
authors.lastname: Yin
authors.forename: Markus A
authors.initials: MA
authors.lastname: Lill
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Danielson
authors.forename: Helene
authors.initials: H
authors.lastname: Freiser
authors.forename: Jianjie
authors.initials: J
authors.lastname: Huang
mesh_terms: D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D002839:Chromans; D016861:Cyclooxygenase Inhibitors; D014810:Vitamin E; C013649:plastochromanol 8; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human