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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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Special Emphasis Panel (ZAT1-SM (23))
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Hopp, Craig
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Purdue University
Other Domestic Higher Education
West Lafayette
United States
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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 γ-Tocotrienol Inhibits Cytokine-Stimulated NF-κB 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, γ-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) γ-Tocotrienol inhibits lipopolysaccharide-induced interlukin-6 and granulocyte colony-stimulating factor by suppressing C/EBPβ and NF-κB in macrophages. J Nutr Biochem 24:1146-52