Essential role of constitutive androstane receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis
Essential role of constitutive androstane receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis
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DOI：
10.1016/j.fct.2015.06.010
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发表时间：
2015-09-01
影响因子：
4.3
通讯作者：
Yoshida, Midori
中科院分区：
文献类型：
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作者：
Maeda, Jun;Inoue, Kaoru;Yoshida, Midori
银杏叶提取物(GBE)是一种常用的草药补充剂。国家毒理学计划(NTP)对GBE的研究报告了明确的证据表明，在小鼠中存在肝癌致癌作用。为了阐明银杏叶提取物(GBE)诱发肝癌的作用机制，我们用CAR基因敲除(CARKO)和野生型(WT)小鼠研究了结构性雄烷受体(CAR)在GBE诱发肝癌过程中的作用。我们使用了与NTP研究使用的相同数量的GBE。在1周的银杏叶提取物饮食治疗中，WT小鼠的肝细胞DNA复制增加，而CARKO小鼠则没有。在4周或13周的治疗中，WT组小鼠的肝脏Cyp2b10诱导和肝细胞肥大明显增加，而银杏叶提取物对CARKO小鼠的这些影响要小得多。在二乙基亚硝胺诱发的两阶段肝癌模型中，银杏叶提取物治疗27周后，WT小鼠的嗜酸性改变灶和腺瘤增加。相比之下，CARKO小鼠的病灶和腺瘤明显不那么明显。这些结果表明银杏叶提取物诱导的肝细胞癌的发生主要是CAR介导的。由于CAR介导的MOA在啮齿动物肝癌发生中的作用被认为在定性上是不可信的，我们的发现将有助于评估GBE对人类的致癌特性。(C)2015爱思唯尔有限公司。保留所有权利。
Ginkgo biloba extract (GBE) is commonly used as a herbal supplement. The National Toxicology Program (NTP) study of GBE reported clear evidence of hepatocarcinogenicity in mice. To clarify the mode of action (MOA) for hepatocarcinogenesis by GBE, we investigated the involvement of the constitutive androstane receptor (CAR) in hepatocarcinogenesis induced by GBE using CAR-knockout (CARKO) and wild type (WT) mice. We used the same lot of GBE that was used for the NTP study. In 1-week GBE dietary treatment, hepatocellular DNA replication was increased in WT mice but not in CARKO mice. In 4-or 13-week treatment, greater hepatic Cyp2b10 induction and hepatocellular hypertrophy were observed in WT mice, whereas these effects of GBE were much smaller in CARKO mice. In a two-stage hepatocarcinogenesis model initiated by diethylnitrosamine, 27-week treatment with GBE resulted in an increase of eosinophilic altered foci and adenomas in WT mice. By contrast, foci and adenomas were clearly less evident in CARKO mice. These results indicate that GBE-induced hepatocarcinogenesis is mainly CAR-mediated. Since CAR-mediated MOA for hepatocarcinogenesis in rodents is considered to be qualitatively implausible for humans, our findings would be helpful to evaluate the carcinogenic characterization of GBE to humans. (C) 2015 Elsevier Ltd. All rights reserved.