Hoenerhoff Mark J, Pandiri Arun R, Snyder Stephanie A, Hong Hue-Hua L, Ton Thai-Vu, Peddada Shyamal, Shockley Keith, Witt Kristine, Chan Po, Rider Cynthia, Kooistra Linda, Nyska Abraham, Sills Robert C
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences and National Toxicology Program, Research Triangle Park, NC 27519, USA.
Toxicol Pathol. 2013 Aug;41(6):826-41. doi: 10.1177/0192623312467520. Epub 2012 Dec 21.
Ginkgo biloba leaf extract (GBE) has been used for centuries in traditional Chinese medicine and today is used as an herbal supplement touted for improving neural function and for its antioxidant and anticancer effects. Herbal supplements have the potential for consumption over extended periods of time, with a general lack of sufficient data on long-term carcinogenicity risk. Exposure of B6C3F1 mice to GBE in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increase in hepatocellular tumors, including hepatocellular carcinoma (HCC). We show that the mechanism of hepatocarcinogenesis in GBE exposed animals is complex, involving alterations in H-ras and Ctnnb1 mutation spectra, WNT pathway dysregulation, and significantly altered gene expression associated with oncogenesis, HCC development, and chronic xenobiotic and oxidative stress compared to spontaneous HCC. This study provides a molecular context for the genetic changes associated with hepatocarcinogenesis in GBE exposed mice and illustrates the marked differences between these tumors and those arising spontaneously in the B6C3F1 mouse. The molecular changes observed in HCC from GBE-treated animals may be of relevance to those seen in human HCC and other types of cancer, and provide important data on potential mechanisms of GBE hepatocarcinogenesis.
银杏叶提取物(GBE)在传统中药中已使用了数百年,如今作为一种草药补充剂,因其改善神经功能以及抗氧化和抗癌作用而受到推崇。草药补充剂有可能长期服用,而关于长期致癌风险的充分数据普遍缺乏。在为期两年的国家毒理学计划致癌性生物测定中,将B6C3F1小鼠暴露于GBE下,导致肝细胞肿瘤(包括肝细胞癌,HCC)出现剂量依赖性增加。我们表明,暴露于GBE的动物中肝癌发生的机制很复杂,涉及H-ras和Ctnnb1突变谱的改变、WNT信号通路失调,以及与肿瘤发生、HCC发展以及与自发HCC相比的慢性异生物素和氧化应激相关的基因表达显著改变。本研究为与暴露于GBE的小鼠肝癌发生相关的基因变化提供了分子背景,并阐明了这些肿瘤与B6C3F1小鼠自发产生的肿瘤之间的显著差异。在接受GBE治疗的动物的HCC中观察到的分子变化可能与人类HCC和其他类型癌症中所见的变化相关,并为GBE肝癌发生的潜在机制提供重要数据。