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

Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20464-9. doi: 10.1073/pnas.0810962106. Epub 2008 Dec 11.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Chromans / pharmacology*
  • Cyclooxygenase 2 / drug effects*
  • Cyclooxygenase Inhibitors*
  • Inhibitory Concentration 50
  • Structure-Activity Relationship
  • Vitamin E / analogs & derivatives*
  • Vitamin E / metabolism*
  • Vitamin E / pharmacology


  • Chromans
  • Cyclooxygenase Inhibitors
  • Vitamin E
  • plastochromanol 8
  • 2,2,5,7,8-pentamethyl-1-hydroxychroman
  • Cyclooxygenase 2
  • PTGS2 protein, human