Hepatocellular Carcinomas in B6C3F1 Mice Treated with Ginkgo biloba Extract for Two Years Differ from Spontaneous Liver Tumors in Cancer Gene Mutations and Genomic Pathways

• Published in: Toxicologic pathology 2013-08, Vol.41 (6), p.826-841
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; beta Catenin - metabolism; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinogenicity Tests; Chemical agents; Cluster Analysis; Dose-Response Relationship, Drug; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - toxicity; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - drug effects; Ginkgo biloba; Ginkgo biloba - chemistry; Immunohistochemistry; Liver - chemistry; Liver - drug effects; Liver - pathology; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutagenicity Tests; Oxidative Stress - drug effects; Reproducibility of Results; Signal Transduction - drug effects; Toxicology; Tumors
• ISSN: 0192-6233; 1533-1601
• DOI: 10.1177/0192623312467520

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.