From the Department of Pharmacology and the Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, Tennessee 37232 and.
the School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
J Biol Chem. 2017 Dec 29;292(52):21243-21252. doi: 10.1074/jbc.RA117.000123. Epub 2017 Nov 2.
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 () of IC 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 , which may explain the wide range of cellular targets, but if bioactivation is insufficient , 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.
姜黄，其活性多酚姜黄素，在传统亚洲医学中作为抗炎疗法已经使用了几个世纪。已经鉴定出姜黄素的许多细胞靶标，但不清楚为什么一种化合物可以影响如此广泛的靶标。在这里，我们确定姜黄素是一种前药，需要氧化激活成反应性代谢物才能发挥抗炎活性。经历氧化转化的合成姜黄素类似物强烈抑制促炎转录因子核因子 κB（NF-κB），而稳定的、不可氧化的类似物则活性较低，IC 对数与自动氧化速率的相关系数 () 为 0.75。抑制谷胱甘肽生物合成，这可以保护细胞免受反应性代谢物的侵害，增加了姜黄素的效力，并减少了细胞中姜黄素-谷胱甘肽加合物的量。姜黄素的氧化代谢物与 NF-κB 激酶亚基β（IKKβ）的抑制剂结合并抑制其活性，IKKβ 是 NF-κB 的上游激活激酶。不稳定的、炔基标记的姜黄素类似物与细胞蛋白大量结合，这些结合物在用姜黄素或不稳定类似物预处理时减少，但用稳定类似物则不会。姜黄素很容易发生生物活化，这可能解释了其广泛的细胞靶标，但如果生物活化不足，也可能有助于解释迄今为止姜黄素在人体研究中不一致的结果。我们得出结论，这里揭示的代谢生物活化范例应该在姜黄素和其他具有药用价值的多酚的临床试验的评估和设计中加以考虑。
