Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 52, Pages 21243-21252Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000123
Keywords
autoxidation; cysteine; electrophile; glutathione; protein adduction; polyphenol; flavonoid; quinone; NF-B; redox regulation
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Funding
- National Institutes of Health from the National Center for Complementary and Integrative Health (NCCIH) [R01AT006896]
- Office of Dietary Supplements (ODS)
- Vanderbilt Institute in Chemical Biology
- National Cancer Institute SPORE in GI Cancer Grant [5P50CA095103]
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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 B (NF-B), whereas stable, non-oxidizable analogs were less active, with a correlation coefficient (R-2) of IC(50)versus 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-B kinase subunit (IKK), an activating kinase upstream of NF-B. 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.
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