Curcumin, a polyphenol isolated from the plant turmeric, is recognized for its antioxidant, anti-inflammatory and anti-tumorigenic bioactivities. t is currently being evaluated in multiple clinical trials for the prevention or treatment of inflammatory and neurodegenerative diseases, and also for intestinal cancers. Although a large number of in vitro targets of curcumin have been identified, the precise chemical-molecular mechanism(s) of its biological activities have not been elucidated. We have discovered a novel, previously unrecognized oxidative transformation of curcumin, and we have detected abundant levels of the oxidative metabolites in plasma and intestinal mucosa after oral administration of curcumin to mice. The oxidative transformation of curcumin is rapid, prominent, and gives rise to novel metabolites via reactive intermediates, including a quinone methide and a spiro-epoxide intermediate. The major final product is a dioxygenated cyclopentadione derivative of curcumin. We will test the hypothesis that the products of oxidative transformation are mediators of pharmacological effects of curcumin.
In Specific Aim 1 we will determine biological consequences of oxidative transformation of curcumin. Specifically, we will analyze the mechanism of inhibition of reduced and oxidized IKK? by electrophilic and nucleophilic curcumin metabolites, the mechanism of induction of DNA cleavage by topoisomerase II, and protein and DNA adduct formation by the quinone methide intermediate.
In Specific Aim 2 we will identify the products and intermediates of oxidative transformation of curcumin and determine their mechanism of formation.
In Specific Aim 3 we will determine in vivo metabolism, tissue distribution, and pharmacokinetics of curcumin and its metabolites using a novel LC-MS methodology with quantification by isotopically labeled standards. The concept of oxidative activation could result in a new paradigm of understanding the structure and function of curcumin with important implications for its clinical application as a therapeutic CAM agent.
Increasing biochemical and clinical evidence supports the use of the dietary supplement curcumin for the prevention of disease. The goal of this application is to characterize the function and formation of products formed from curcumin in the body that could be involved in its biological activity.
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|Giménez-Bastida, Juan A; Shibata, Takahiro; Uchida, Koji et al. (2017) Roles of 5-lipoxygenase and cyclooxygenase-2 in the biosynthesis of hemiketals E2 and D2 by activated human leukocytes. FASEB J 31:1867-1878|
|Edwards, Rebecca L; Luis, Paula B; Varuzza, Paolo V et al. (2017) The anti-inflammatory activity of curcumin is mediated by its oxidative metabolites. J Biol Chem 292:21243-21252|
|Gordon, Odaine N; Luis, Paula B; Ashley, Rachel E et al. (2015) Oxidative Transformation of Demethoxy- and Bisdemethoxycurcumin: Products, Mechanism of Formation, and Poisoning of Human Topoisomerase II?. Chem Res Toxicol 28:989-96|
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