Different forms of vitamin E and metabolite 13′-carboxychromanols inhibit cyclooxygenase-1 and its catalyzed thromboxane in platelets, and tocotrienols and 13'-carboxychromanols are competitive inhibitors of 5-lipoxygenase

Cyclooxygenase (COX-1 and COX-2)-and 5-lipoxygenase (5-LOX)-catalyzed biosynthesis of eicosanoids play important roles in inflammation and chronic diseases. The vitamin E family has four tocopherols and tocotrienols. We have shown that the metabolites of delta-tocopherol (delta T) and delta-tocotrienol (delta TE), i.e., delta T-13'-carboxychromanol (COOH) and delta TE-13'-COOH, respectively, inhibit COX-1/-2 and 5-LOX activity, but the nature of how they inhibit 5-LOX is not clear. Further, the impact of tocopherols and tocotrienols on COX-1/-2 or 5-LOX activity has not been fully delineated. In this study, we found that tocopherols and tocotrienols inhibited human recombinant COX-1 with IC50s of 1-12 mu M, and suppressed COX-1-mediated formation of thromboxane in collagen-stimulated rat's platelets with IC50s of 8-50 mu M. None of the vitamin E forms directly inhibited COX-2 activity. 13'-COOHs inhibited COX-1 and COX-2 enzyme activity with IC50s of 3-4 and 4-10 mu M, respectively, blocked thromboxane formation in collagen-and ionophore-stimulated rats' platelets with IC50s of 1.5-2.5 mu M, and also inhibited COX-2-mediated prostaglandins in stimulated cells. Using enzyme kinetics, we observed that delta T-13'-COOH, delta TE-13'-COOH and delta TE competitively inhibited 5-LOX activity with Ki of 1.6, 0.8 and 2.2 mu M, respectively. These compounds decreased leukotriene B 4 from stimulated neutrophil-like cells without affecting translocation of 5-LOX from cytosol to the nucleus. Our study reveals inhibitory effects of vitamin E forms and 13'-COOHs on COX-1 activity and thromboxane formation in platelets, and elucidates mechanisms underlying their inhibition of 5-LOX. These observations are useful for understanding the role of these compounds in disease prevention and therapy. (C) 2021 Elsevier Inc. All rights reserved.