Anti-inflammatory mechanisms, pharmacokinetics of novel metabolites of vitamin E

维生素E新型代谢物的抗炎机制、药代动力学

基本信息

批准号：
8196666
负责人：
Qing Jiang
金额：
$ 30.8万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8196666
关键词：
Address Adjuvant Arthritis Anti-Inflammatory Agents Anti-inflammatory Antioxidants Arachidonate 5-Lipoxygenase Area Arthritis Biological Assay Biological Availability Calcium Carrageenan Cells Clinical Clinical Research Complementary and alternative medicine Complex Data Dinoprostone Disease Drug Kinetics Environment Enzymes Exhibits Generations Health Benefit Ibuprofen In Vitro Inflammation Inflammatory Ionophores LOX gene Lead Leukotriene B4 Lipoxygenase Inhibitors Measurement Measures Mediating Methods Modeling Nature New Territories Non-Steroidal Anti-Inflammatory Agents Outcome PTGS2 gene Pain management Pathway interactions Pharmaceutical Preparations Play Production Property Prostaglandin-Endoperoxide Synthase Rattus Reaction Research Role Sensitivity and Specificity Signal Transduction Supplementation Testing Therapeutic Effect Time Tocopherols Translating Vitamin E Vitamins Work Zileuton analog antiarthritic agent base celecoxib clinical efficacy comparative efficacy cyclooxygenase 1 improved in vivo neutrophil non-drug novel pre-clinical prophylactic success

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：维生素 E 补充剂已普遍用作 CAM（补充和替代医学）。维生素 E 的临床研究专门针对 1-生育酚 (1T)，但在潜在的健康益处方面却得出了令人失望的结果。然而，我们和其他人已经证明，其他维生素 E 形式，尤其是它们的新型代谢物，具有 1T 所不具备的独特抗炎特性。特别是，我们已经证明 13'-羧基苯并二氢吡喃醇 (4-13'-COOH) 是一种源自 4-生育酚 (4T) 的长链代谢物，可抑制环氧合酶（COX-1 和 COX-2）和 5-脂氧合酶（ 5-LOX），其效力类似于布洛芬（一种常用的非类固醇抗炎药 - NSAID）和齐留通（一种临床使用的药物） 5-LOX抑制剂），分别。同时，3-生育酚 (3T) 和 4T（而非 1T）抑制细胞中 COX-2 介导的前列腺素 E2 生成，并通过阻止钙流入来抑制中性粒细胞中 5-LOX 介导的白三烯 B4 生成。在一项初步研究中，我们发现 4T 具有良好的抗关节炎作用。由于这些维生素 E 形式和代谢物同时抑制 COX 和 5-LOX 介导的促炎途径，因此我们认为这些化合物作为抗炎和抗关节炎药物可能优于常用的 NSAID，因为大多数 NSAID 只抑制 COX-催化途径。此外，由于对 COX 和 5-LOX 的抑制作用更强，我们认为 13'-COOH 可能比未代谢的维生素更有效。为了检验这些假设，我们将 1) 研究长链羧基苯并二氢吡喃醇对细胞和酶研究中 COX-1/-2 和 5-LOX 催化反应的影响和机制，2) 开发一种新的 LC-MS -MS 测定维生素 E 代谢物并表征 4-13'-COOH、3T 和 4T 的药代动力学，3) 转化独特的抗炎活性在大鼠炎症模型中体外观察到 4-13'-COOH 和维生素 E 形式，并将其抗炎功效与已建立的 NSAID 进行比较，4) 通过研究 4-13'-COOH 和维生素 E 的抗关节炎功效，将抗炎作用转化为疾病相关模型大鼠佐剂诱导的关节炎模型中的 4-13'-COOH、3T 和 4T。我们对这些维生素 E 形式及其新型代谢物的研究可能会发现一类新型抗炎药物，这种药物可能比一些常用的抗炎药物更安全，但具有相似或更好的功效。拟议的研究将阐明抗炎作用机制，并产生重要的临床前数据，以确保对这些化合物进行尽可能信息丰富的临床疗效研究。公共健康相关性：本申请将检验特定维生素 E 形式及其新型代谢物长链羧基苯并二氢吡喃醇可能是有效的新型抗炎和抗关节炎药物的假设。这项研究可能会发现比常用的非甾体抗炎药更好的治疗炎症性疾病的疗法，因此可能导致用维生素 E 代谢物替代非甾体抗炎药或将其与非甾体抗炎药联合用于关节炎和疼痛治疗（这是一个临床重要领域）。