Luis Paula B, Gordon Odaine N, Nakashima Fumie, Joseph Akil I, Shibata Takahiro, Uchida Koji, Schneider Claus
Department of Pharmacology (Clinical Pharmacology) and Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Graduate School of Bioagricultural Sciences, Division of Biofunctional Chemistry, Nagoya University, Nagoya 464-8601, Japan.
Biochem Pharmacol. 2017 May 15;132:143-149. doi: 10.1016/j.bcp.2017.03.002. Epub 2017 Mar 6.
Conjugation with glucuronic acid is a prevalent metabolic pathway of orally administrated curcumin, the bioactive diphenol of the spice turmeric. The major in vitro degradation reaction of curcumin is autoxidative transformation resulting in oxygenation and cyclization of the heptadienedione chain to form cyclopentadione derivatives. Here we show that curcumin-glucuronide is much more stable than curcumin, degrading about two orders of magnitude slower. Horseradish peroxidase-catalyzed oxidation of curcumin-glucuronide occurred at about 80% of the rate with curcumin, achieving efficient transformation. Using LC-MS and NMR analyses the major products of oxidative transformation were identified as glucuronidated bicyclopentadione diastereomers. Cleavage into vanillin-glucuronide accounted for about 10% of the products. Myeloperoxidase and lactoperoxidase oxidized curcumin-glucuronide whereas tyrosinase and xanthine oxidase were not active. Phorbol ester-activated primary human leukocytes showed increased oxidative transformation of curcumin-glucuronide which was inhibited by the peroxidase inhibitor sodium azide. These studies provide evidence that the glucuronide of curcumin is not an inert product and may undergo further enzymatic and non-enzymatic metabolism. Oxidative transformation by leukocyte myeloperoxidase may represent a novel metabolic pathway of curcumin and its glucuronide conjugate.
与葡糖醛酸结合是口服姜黄素（姜黄这种香料中的生物活性双酚）的一种普遍代谢途径。姜黄素在体外的主要降解反应是自氧化转化，导致庚二烯二酮链发生氧化和环化，形成环戊二酮衍生物。在此我们表明，姜黄素葡糖醛酸酯比姜黄素稳定得多，降解速度慢约两个数量级。辣根过氧化物酶催化的姜黄素葡糖醛酸酯氧化反应速率约为姜黄素的80%，实现了高效转化。通过液相色谱 - 质谱联用（LC - MS）和核磁共振（NMR）分析，氧化转化的主要产物被鉴定为葡糖醛酸化的双环戊二酮非对映异构体。裂解生成香草醛葡糖醛酸酯约占产物的10%。髓过氧化物酶和乳过氧化物酶可氧化姜黄素葡糖醛酸酯，而酪氨酸酶和黄嘌呤氧化酶无活性。佛波酯激活的原代人白细胞显示姜黄素葡糖醛酸酯的氧化转化增加，该反应受到过氧化物酶抑制剂叠氮化钠的抑制。这些研究提供了证据，表明姜黄素的葡糖醛酸酯不是一种惰性产物，可能会经历进一步的酶促和非酶促代谢。白细胞髓过氧化物酶介导的氧化转化可能代表了姜黄素及其葡糖醛酸酯共轭物的一种新的代谢途径。
