Vitamin E supplementation has been commonly used as a CAM (Complementary and Alternative Medicine). Clinical studies on vitamin E have focused exclusively on 1-tocopherol (1T), but they have yielded disappointing results regarding potential health benefits. However, we and others have shown that other vitamin E forms and especially their novel metabolites have unique anti-inflammatory properties that are not possessed by 1T. In particular, we have demonstrated that 13'-carboxychromanol (4-13'-COOH), a long-chain metabolite derived from 4- tocopherol (4T), inhibits cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) with potency similar to ibuprofen (a commonly used non-steroid anti-inflammatory drugs - NSAID) and zileuton (a clinically used 5-LOX inhibitor), respectively. Meanwhile, 3-tocopherol (3T) and 4T, but not 1T, inhibited COX-2-mediated prostaglandin E2 generation in cells and suppressed 5-LOX-mediated leukotriene B4 production in neutrophils by blocking calcium influx. In a preliminary study, we have found that 4T exhibited promising anti-arthritis effects. Since these vitamin E forms and metabolites inhibit both COXs- and 5-LOX-mediated pro-inflammatory pathways, we propose that these compounds may be superior to commonly used NSAIDs as anti-inflammatory and anti-arthritis agents because most NSAIDs only inhibit COX- catalyzed pathway. In addition, due to stronger inhibition of COXs and 5-LOX, we propose that 13'-COOH may be more effective than un-metabolized vitamins. To test these hypotheses, we will 1) investigate the effect and mechanism of long-chain carboxychromanols on COX-1/-2 and 5-LOX-catalyzed reactions in cell- and enzyme-based studies, 2) develop a new LC-MS-MS assay for vitamin E metabolites and characterize the pharmacokinetics of 4-13'-COOH, 3T and 4T, 3) translate the unique anti-inflammatory activity of 4-13'-COOH and vitamin E forms observed in vitro to a rat inflammation model and compare their anti-inflammatory efficacy to established NSAIDs, and 4) translate the anti-inflammatory actions to a disease relevant model by investigating anti-arthritis efficacy of 4-13'-COOH, 3T and 4T in the rat adjuvant-induced arthritis model. Our studies on these vitamin E forms and their novel metabolites may lead to discovery of a new class of anti-inflammatory agents that may be safer than some commonly used anti-inflammatory drugs and yet have similar or superior efficacy. The proposed studies will elucidate mechanisms of anti-inflammatory action and generate important preclinical data that are needed to insure maximally informative clinical efficacy studies on these compounds.
This application will test the hypothesis that specific vitamin E forms and their novel metabolites, long-chain carboxychromanols, may be effective novel anti-inflammatory and anti-arthritis agents. This study may lead to discovery of superior therapy for treatment of inflammatory diseases over commonly used NSAIDs and therefore may result in NSAID replacement with vitamin E metabolites or their combination with NSAIDs in arthritis and pain management, a clinically important area.
|Jang, Yumi; Park, Na-Young; Rostgaard-Hansen, Agnetha Linn et al. (2016) Vitamin E metabolite 13'-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice. Free Radic Biol Med 95:190-9|
|Jiang, Qing; Xu, Tianlin; Huang, Jianjie et al. (2015) Analysis of vitamin E metabolites including carboxychromanols and sulfated derivatives using LC/MS/MS. J Lipid Res 56:2217-25|
|Wang, Yun; Park, Na-Young; Jang, Yumi et al. (2015) Vitamin E Î³-Tocotrienol Inhibits Cytokine-Stimulated NF-ÎºB Activation by Induction of Anti-Inflammatory A20 via Stress Adaptive Response Due to Modulation of Sphingolipids. J Immunol 195:126-33|
|Jiang, Qing (2014) Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy. Free Radic Biol Med 72:76-90|
|Jiang, Qing; Jiang, Ziying; Hall, Yava Jones et al. (2013) Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice. Free Radic Biol Med 65:1069-77|
|Hernandez, Michelle L; Wagner, James G; Kala, Aline et al. (2013) Vitamin E, Î³-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers. Free Radic Biol Med 60:56-62|
|Wang, Yun; Jiang, Qing (2013) Î³-Tocotrienol inhibits lipopolysaccharide-induced interlukin-6 and granulocyte colony-stimulating factor by suppressing C/EBPÎ² and NF-ÎºB in macrophages. J Nutr Biochem 24:1146-52|