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J Biol Chem. 2017 Dec 29;292(52):21243-21252. doi: 10.1074/jbc.RA117.000123. Epub 2017 Nov 2.

The anti-inflammatory activity of curcumin is mediated by its oxidative metabolites.

Author information

1
From the Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232 and.
2
the School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
3
From the Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232 and claus.schneider@vanderbilt.edu.

Abstract

The spice turmeric, with its active polyphenol curcumin, has been used as anti-inflammatory remedy in traditional Asian medicine for centuries. Many cellular targets of curcumin have been identified, but how such a wide range of targets can be affected by a single compound is unclear. Here, we identified curcumin as a pro-drug that requires oxidative activation into reactive metabolites to exert anti-inflammatory activities. Synthetic curcumin analogs that undergo oxidative transformation potently inhibited the pro-inflammatory transcription factor nuclear factor κB (NF-κB), whereas stable, non-oxidizable analogs were less active, with a correlation coefficient (R2) of IC50versus log of autoxidation rate of 0.75. Inhibition of glutathione biosynthesis, which protects cells from reactive metabolites, increased the potency of curcumin and decreased the amount of curcumin-glutathione adducts in cells. Oxidative metabolites of curcumin adducted to and inhibited the inhibitor of NF-κB kinase subunit β (IKKβ), an activating kinase upstream of NF-κB. An unstable, alkynyl-tagged curcumin analog yielded abundant adducts with cellular protein that were decreased by pretreatment with curcumin or an unstable analog but not by a stable analog. Bioactivation of curcumin occurred readily in vitro, which may explain the wide range of cellular targets, but if bioactivation is insufficient in vivo, it may also help explain the inconclusive results in human studies with curcumin so far. We conclude that the paradigm of metabolic bioactivation uncovered here should be considered for the evaluation and design of clinical trials of curcumin and other polyphenols of medicinal interest.

KEYWORDS:

NF-κB; autoxidation; cysteine; electrophile; flavonoid; glutathione; polyphenol; protein adduction; quinone; redox regulation

PMID:
29097552
PMCID:
PMC5766941
DOI:
10.1074/jbc.RA117.000123
[Indexed for MEDLINE]
Free PMC Article

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