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-1␤-stimulated A549 cells without affecting COX-2 expression, showing the relative potency of ␥-tocotrienol Ϸ ␦-tocopherol > ␥-tocopherol Ͼ Ͼ ␣-or ␤-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 M 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 M, 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 M, 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.cancer ͉ inflammation ͉ PGE2 ͉ tocopherol ͉ tocotrienol C yclooxygenases (COX-1 and COX-2) catalyze the conversion of arachidonic acid (AA) to prostaglandin H 2 (PGH 2 ), the common precursor to prostaglandins and thromboxanes that are important lipid mediators for regulation of many physiological and pathophysiological responses (1). COXs are bifunctional enzymes that carry out two sequential activities-i.e., the cyclooxygenase activity, which leads to the formation of prostaglandin G 2 (PGG 2 ), and the peroxidase activity, which reduces PGG 2 to PGH 2 (2). COX-1 is constitutively expressed in many tissues, including platelets where thromboxanes are generated by this enzyme to promote platelet aggregation. COX-2 is often induced under acute/chronic inflammatory conditions and is mainly responsible for the generation of proinflammatory eicosanoids, including prostaglandin E 2 (PGE 2 ) (3). COX inhibitors, which are nonsteroidal anti-inflammatory drugs (NSAIDs), have been used for the relief of fever, pain, and inflammation (4). Chronic inflammation has been identified as a significant factor in the development of cancer (5). It is well established that NSAIDs are effective chemoprevention agents for cancer (6), although their long-term use has been questioned due to the associated gastrointestinal sid...

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

“…These metabolites are rapidly processed by the metabolic machinery of liver cells to form the end product CEHC, and thus their levels in the circulation are extremely low, but their potency as in vitro antiinflammatory and pro-apoptotic agents was proposed to be much stronger than that of CEHCs. Actually, long-chain metabolites, and particularly 13 0 -carboxychromanol, have been recently identified to possess inhibitory effects on cyclooxygenase activity (Jiang et al 2008), which may be consistent with the proposed anti-inflammatory activity of T3 (Elangovan et al 2008;Yam et al 2009), and to promote oxidative stress and pro-apoptotic effects in HepG2 cells .…”

Present trends in vitamin E research

“…The formation of a complex and a possible competitive inhibition by a-tocopherol were described for phospholipase A2 isoenzymes [24,25], and other mechanisms that include the control of substrate and cofactor availability could be responsible of the modulation of COX-2, 5-lipoxygenase and cPLA 2 (reviewed in [19,26]). The c form of vitamin E and more recently long chain metabolites were confirmed to be the most efficient COX-2 inhibitors in vitro and in vivo [5].…”

“…Intracellular players in signaling expected to be influenced by the interaction between these proteins and vitamin E are numerous (reviewed in [4][5][6][7]) and include kinases such as PKC, Akt/PKB, some members of MAPK family and cell cycle related kinases, and the recently proposed downstream components of the death domain and proteins of the endoplasmic reticulum stress signaling [8]. Tocotrienols have been reported to be ligands of the estrogen receptor b (ERb) [9] that could thus contribute some aspects of vitamin E signaling that will be further discussed later in the section dedicated to tocotrienols.…”

“…These functions occur through signaling effects that CEHC metabolites produce with a close analogy with their vitamin E precursors (reviewed in [7,27,29]). Other than for the final products of vitamin E metabolism CEHCs, signaling effects have been more recently described in the case of long chain metabolites that are present in the circulation and are formed preferentially in some cell lines such as A549 alveolar type II epithelial cells [5].…”

Metabolism of tocotrienols in animals and synergistic inhibitory actions of tocotrienols with atorvastatin in cancer cells

“…Recent studies show that the metabolites of vitamin E may also contribute to the biological effects of vitamin E (Jiang et al 2008;Birringer et al 2010). Therefore, it is important to understand the metabolism of vitamin E. Although the metabolism of tocopherols has been extensively investigated, studies on the metabolism of T3s are limited.…”