1. Essential role of constitutive androstane receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis.
- Author
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Maeda J, Inoue K, Ichimura R, Takahashi M, Kodama Y, Saito N, and Yoshida M
- Subjects
- Adenoma, Liver Cell chemically induced, Adenoma, Liver Cell etiology, Adenoma, Liver Cell metabolism, Adenoma, Liver Cell pathology, Animals, Aryl Hydrocarbon Hydroxylases chemistry, Aryl Hydrocarbon Hydroxylases genetics, Aryl Hydrocarbon Hydroxylases metabolism, Carcinogens chemistry, Carcinogens toxicity, Cocarcinogenesis pathology, Constitutive Androstane Receptor, Cytochrome P-450 Enzyme Inducers adverse effects, Cytochrome P450 Family 2, DNA Replication, Diethylnitrosamine agonists, Diethylnitrosamine toxicity, Hepatomegaly metabolism, Hepatomegaly pathology, Japan, Liver drug effects, Liver metabolism, Liver pathology, Liver Neoplasms chemically induced, Liver Neoplasms metabolism, Liver Neoplasms pathology, Male, Mice, Inbred C3H, Mice, Knockout, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism, Steroid Hydroxylases chemistry, Steroid Hydroxylases genetics, Steroid Hydroxylases metabolism, Toxicity Tests, Subchronic, Cocarcinogenesis metabolism, Dietary Supplements adverse effects, Ginkgo biloba chemistry, Hepatomegaly etiology, Liver Neoplasms etiology, Plant Extracts adverse effects, Receptors, Cytoplasmic and Nuclear agonists
- Abstract
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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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