Department of Biology, Georgia State University, Atlanta, GA-30303, USA.
ReaGene Biosciences Private Limited, Bengaluru, India.
Sci Rep. 2018 Feb 14;8(1):3056. doi: 10.1038/s41598-018-21125-2.
Anticancer efficacy of ginger phenolics (GPs) has been demonstrated in various in vitro assays and xenograft mouse models. However, only sub-therapeutic plasma concentrations of GPs were detected in human and mouse pharmacokinetic (PK) studies. Intriguingly, a significant portion of GPs occurred as phase II metabolites (mainly glucuronide conjugates) in plasma. To evaluate the disposition of GPs and understand the real players responsible for efficacy, we performed a PK and tissue distribution study in mice. Plasma exposure of GPs was similar on day 1 and 7, suggesting no induction or inhibition of clearance pathways. Both free and conjugated GPs accumulated in all tissues including tumors. While non-cytotoxicity of 6-ginerol glucuronide precluded the role of conjugated GPs in cell death, the free forms were cytotoxic against prostate cancer cells. The efficacy of ginger was best explained by the reconversion of conjugated GPs to free forms by β-glucuronidase, which is over-expressed in the tumor tissue. This previously unrecognized two-step process suggests an instantaneous conversion of ingested free GPs into conjugated forms, followed by their subsequent absorption into systemic circulation and reconversion into free forms. This proposed model uncovers the mechanistic underpinnings of ginger's anticancer activity despite sub-therapeutic levels of free GPs in the plasma.
姜酚类化合物（GPs）的抗癌功效已在各种体外检测和异种移植小鼠模型中得到证实。然而，在人体和小鼠药代动力学（PK）研究中仅检测到亚治疗血浆浓度的 GPs。有趣的是，GPs 的很大一部分以血浆中的 II 期代谢物（主要是葡萄糖醛酸缀合物）形式存在。为了评估 GPs 的处置情况并了解对功效有实际影响的因素，我们在小鼠中进行了 PK 和组织分布研究。GPs 的血浆暴露在第 1 天和第 7 天相似，表明没有清除途径的诱导或抑制。游离和共轭 GPs 均在所有组织（包括肿瘤）中蓄积。虽然 6-姜烯醇葡萄糖醛酸无细胞毒性排除了共轭 GPs 在细胞死亡中的作用，但游离形式对前列腺癌细胞具有细胞毒性。由于 β-葡萄糖醛酸酶将共轭 GPs 重新转化为游离形式，从而使姜的功效最佳，而 β-葡萄糖醛酸酶在肿瘤组织中过度表达。尽管游离 GPs 在血浆中的浓度低于治疗浓度，但这种以前未被认识的两步过程表明，摄入的游离 GPs 会立即转化为共轭形式，随后被吸收到全身循环中并重新转化为游离形式。该模型揭示了姜的抗癌活性的机制基础，尽管游离 GPs 的血浆浓度低于治疗浓度。
