Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent
Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent
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DOI：
10.1038/s41598-018-21125-2
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发表时间：
2018-02-14
影响因子：
4.6
通讯作者：
Aneja, Ritu
中科院分区：
文献类型：
--
作者：
Mukkavilli, Rao;Yang, Chunhua;Aneja, Ritu
生姜酚类化合物（GPs）的抗癌功效已在各种体外试验和异种移植小鼠模型中得到证实。然而，在人类和小鼠药代动力学（PK）研究中仅检测到GP的亚治疗血浆浓度。有趣的是，相当一部分GP作为II相代谢产物（主要是葡糖苷酸结合物）出现在血浆中。为了评价GP的分布并了解负责疗效的真实的参与者，我们在小鼠中进行了PK和组织分布研究。GP的血浆暴露在第1天和第7天相似，表明没有诱导或抑制清除途径。游离和结合的GP在包括肿瘤在内的所有组织中积累。虽然6-姜油醇葡糖苷酸的非细胞毒性排除了结合GP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。生姜的功效最好通过β-葡萄糖醛酸酶将缀合的GP再转化为游离形式来解释，β-葡萄糖醛酸酶在肿瘤组织中过度表达。这种以前未被认识到的两步过程表明，摄入的游离GP瞬时转化为缀合形式，随后被吸收到体循环中并再转化为游离形式。该模型揭示了生姜抗癌活性的机制基础，尽管血浆中游离GP的水平低于治疗水平。
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 beta-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.