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.
This study investigates the effects of tocotrienol (TT) or alpha-tocopherol (TF) supplementation on corticosterone level, noradrenalin level and gastric lesions in rats exposed to restraint stress. Twenty-four male Sprague Dawley rats were randomly assigned into 4 equally sized groups; two control groups were given olive oil, while the treated group was supplemented with either tocotrienol of tocopherol orally at a dose of 60 mg/kg body weight. After 28 days of treatment, one control group, TT group and TF group were subjected to restraint stress, 2 hours daily for 4 consecutive days. After the last exposure to stress, plasma samples were taken to determine the corticosterone and noradrenalin levels, after which the rats were sacrificed. The stomach was excised for the evaluation of gastric lesions. Our findings showed that TT and TF were able to maintain the corticosterone level to the prestress values, while only TT was able to maintain the noradrenalin level in rats exposed to stress. Tocotrienol was found to be better in preventing formation of gastric lesions compared to TF. As a conclusion, the protective effect of vitamin E was related to the ability to inhibit stress induced elevation of corticosterone and noradrenalin levels.