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5-Lipoxygenase as immunoregulatory target of human endogenous vitamin E metabolites

Subject Area Pharmacy
Term from 2017 to 2019
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 378292525
 
Final Report Year 2021

Final Report Abstract

Vitamin E is a vital fat-soluble antioxidant, which protects cellular lipids from oxidative damage and possesses anti-inflammatory activity. Vitamin E deficiency is causative for severe degenerative diseases and a decline of the immune response. Supplementation of vitamin E above the recommended daily dose shows marked anti-inflammatory, anti-atherosclerotic, and antitumor efficacy. However, human clinical intervention studies provided mixed results. One possible explanation is that individual differences in metabolism determine the dynamic levels and distribution of vitamin E metabolites and that these molecules are the actual bioactive principles. During the last years, evidence increased that ω-oxidized long-chain vitamin E metabolites (LCM) inhibit 5-lipoxygenase (5-LO) and thus suppress the formation of potent immunomodulatory lipid mediators (leukotrienes). Major open questions were the structural requirements that are essential for 5-LO inhibition, the localization of the LCM binding site at 5-LO, and the physiological relevance of this interaction. The work here carried out suggests that the anti-inflammatory activity of vitamin E (at standard diet without supplementation) is essentially mediated by two LCM, which allosterically inhibit 5-LO at low nanomolar concentrations under physiological conditions, thereby reducing leukotriene-driven inflammatory processes. Specific LCM seem additionally to foster the resolution of inflammation by elevating the systemic level of specialized pro-resolving lipid mediators (SPM), which was surprising. LCM are produced from vitamin E in liver, accumulate in immune cells at sites of inflammation, and reach plasma concentrations that inhibit 5-LO in human leukocytes. In experimental murine peritonitis and asthma, LCM suppressed the inflammatory reaction and prevented bronchial hyperreactivity. Starting from an in-house library, structural features of LCM were identified that determine 5-LO inhibition. Of particular importance is the requirement for terminally functionalized side chains, e.g., ω-carboxylic acids, ω-amides, or ω-alcohols. LCM directly, reversibly, and, at low concentrations, selectively inhibit 5-LO, seemingly by targeting a so far uncharacterized cavity between catalytic and regulatory subunit. At higher concentration, additional enzymes and pathways relevant for inflammation are regulated (e.g., COX-1, mPGES-1, iNOS). Taken together, immune regulatory and anti-inflammatory functions of vitamin E depend on its endogenous metabolites, potentially through inhibiting 5-lipoxygenase in immune cells. The discovery of bioactive endogenous vitamin E metabolites will shed new light on the knowledge about vitamin E acquired during the last 100 years and provides an explanation for the unusual high number of contradictory findings in clinical vitamin E research. Moreover, the results highlight the need for personalized recommendations on vitamin E supplementation and provide a basis for the development of LCM-inspired drug candidates that are orally active, enriched in immune cells at inflammatory sites, and differ in metabolic stability depending on side chain modification. Wann Vitamin E wirkt und wann nicht (NTV) https://www.n-tv.de/wissen/Wann-Vitamin-E-wirkt-und-wann-nicht-article20654535.html, Vitamin E wirkt nicht bei jedem (Focus) https://www.focus.de/wissen/natur/vitamin-e-wirkt-nicht-bei-jedem_id_9722742.html Die Wirkung von Vitamin E ist oft reiner Zufall (Der Standard) https://www.derstandard.de/story/2000088651515/die-wirkung-von-vitamin-e-ist-oft-reiner-zufall Jenaer Wissenschaftler setzen auf neue Wirkstoffe gegen entzündliche Erkrankungen wie Asthma (Thüringer Allgemeine) https://www.thueringer-allgemeine.de/leben/wissenschaft/jenaer-wissenschaftler-setzen-auf-neue-wirkstoffe-gegen-entzuendliche-erkrankungen-wie-asthma-id224716741.html Warum es beim einen wirkt, und beim anderen nicht (Pharmazeutische Zeitung) https://www.pharmazeutische-zeitung.de/warum-es-beim-einem-wirkt-beim-anderen-nicht/ Effects of Vitamin E more diverse than thought (TechExplorist) https://www.techexplorist.com/effects-vitamin-e-more-diverse-thought/17496/ Vitamin E wirkt - aber nicht bei jedem (NetDoktor) https://www.netdoktor.de/news/vitamin-e-wirkt-aber-nicht-bei-jedem/

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