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Oxidative metabolism of curcumin: Products, mechanisms, and biological activity

 

Odaine Gordon1, odaine.gordon@gmail.com, Adam C Ketron2, Neil Osheroff2, Claus Schneider1. (1) Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37235, United States, (2) Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37235, United States

The dietary polyphenol curcumin shows great promise as an anti-cancer and anti-inflammatory agent. While many cellular targets of curcumin have been identified, the chemical mechanisms whereby these targets are affected remain unclear. Orally administered curcumin undergoes metabolic conjugation with glucuronic acid and reduction of the dienone double bonds. We have recently described oxidative transformation of curcumin in vitro leading to a dioxygenated bicyclopentadione derivative as the final product. In contrast to previous hypotheses on the reduced metabolites of curcumin, we proposed that the oxidative metabolites of curcumin are direct mediators of its biological effects.

We synthesized 14C-curcumin and used it to detect and isolate nine novel oxidized metabolites, including three intermediates of the reaction. These metabolites were identified by UV spectroscopy, mass spectrometry, and a combination of 1D and 2D NMR methods. Using the structural data from these molecules combined with H218O isotopic studies we propose a mechanism of oxidative transformation of curcumin through reactive quinone methide and epoxy intermediates. The final products incorporate two oxygen atoms and possess a common nucleophilic β-diketo moiety. We further showed that the phenolic glucuronide of curcumin undergoes the same enzymatic oxidative transformation in vitro to generate the bicyclopentadione-glucuronide.

In biological studies, using a recombinant enzyme in vitro, we showed that autoxidative activation of curcumin is required for its topoisomerase poisoning activity. Further, we detected the final bicyclopentadione product in human and mouse plasma after oral administration of curcumin, indicating oxidative transformation is prominent in vivo. These data support the hypothesis that oxidative metabolites of curcumin are direct mediators of some of its bioactivity. Altogether, our studies for the first time detail the major products of curcumin oxidative transformation and their mechanisms of formation.

Supported by NIH awards F31 AT007287, R01 AT006896

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