Chemopreventive efficacy of oral curcumin: a prodrug hypothesis.
Chemopreventive efficacy of oral curcumin: a prodrug hypothesis.
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口服姜黄素的化学预防功效：前药假设。
DOI：
10.1096/fj.201900166r
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Panyam,Jayanth
中科院分区：
文献类型：
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作者：
Liu,Garvey;Khanna,Vidhi;Kirtane,Ameya;Grill,Alex;Panyam,Jayanth
口服姜黄素，一种天然多酚，与降低癌症发病率有关。然而，大量口服给药的化合物在粪便中消除，并且大部分吸收的化合物代谢为无活性的葡糖苷酸，导致生物利用度差（<1%）。目前尚不清楚口服姜黄素如何表现出化学预防活性。我们提出姜黄素葡糖苷酸是一种炎症反应性天然前药，可在作用部位按需转化回姜黄素。我们的研究显示，在人乳腺癌中，β-葡萄糖醛酸苷酶（一种水解葡萄糖醛酸苷的糖苷键以生成母体化合物的酶）水平升高。在小鼠肿瘤模型中口服姜黄素产生显著的多酚肿瘤水平。静脉注射葡糖苷酸导致肿瘤组织中姜黄素的形成。在具有高β-葡萄糖醛酸酶活性的肿瘤模型中，长期每日口服姜黄素给药导致姜黄素的肿瘤蓄积和肿瘤生长抑制。总的来说，这里提出的研究为口服姜黄素的新作用机制提供了初步证据。Liu，G.，卡纳，五，Kirtane，A.，Grill，A.，Panyam，J.口服姜黄素的化学预防功效：前药假说。FASEB J. 33，9453-9465（2019）。www.fasebj.org
Oral consumption of curcumin, a natural polyphenol, is associated with reduced incidence of cancer. Yet, a significant amount of the orally dosed compound is eliminated in the feces, and a major fraction of the absorbed compound is metabolized to inactive glucuronides, resulting in poor bioavailability (<1%). It is not known how oral curcumin exhibits chemopreventive activity. We propose curcumin glucuronide is an inflammation‐responsive natural prodrug that is converted back to curcumin on demand at the site of action. Our studies show elevated levels of β‐glucuronidase, an enzyme that hydrolyzes the glycosidic bond of glucuronides to generate the parent compound, in human breast cancer. Oral administration of curcumin in mouse tumor models generated significant tumor levels of the polyphenol. Intravenous administration of the glucuronide resulted in the formation of curcumin in the tumor tissue. Chronic daily oral curcumin dosing led to tumor accumulation of curcumin and inhibition of tumor growth in tumor models with high β‐glucuronidase activity. Overall, the study presented here provides preliminary evidence for a novel mechanism of action for orally administered curcumin.—Liu, G., Khanna, V., Kirtane, A., Grill, A., Panyam, J. Chemopreventive efficacy of oral curcumin: a prodrug hypothesis. FASEB J. 33, 9453–9465 (2019). www.fasebj.org