title: Essential role of constitutive androstane receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis.
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.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan; Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ichimura
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Toxicology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan. Electronic address: midoriy@nihs.go.jp.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity; D003043:Cocarcinogenesis / Q000378:metabolism* / Q000473:pathology; D000090702:Constitutive Androstane Receptor; D065693:Cytochrome P-450 Enzyme Inducers / Q000009:adverse effects; D000072467:Cytochrome P450 Family 2; D004261:DNA Replication; D019587:Dietary Supplements / Q000009:adverse effects*; D004052:Diethylnitrosamine / Q000819:agonists / Q000633:toxicity; D020441:Ginkgo biloba / Q000737:chemistry*; D006529:Hepatomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007564:Japan; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010936:Plant Extracts / Q000009:adverse effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059550:Toxicity Tests, Subchronic
chemical_list: D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; D065693:Cytochrome P-450 Enzyme Inducers; D010936:Plant Extracts; D018160:Receptors, Cytoplasmic and Nuclear; D004052:Diethylnitrosamine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2
keywords: Constitutive androstane receptor (CAR); Ginkgo biloba extract (GBE); Hepatocarcinogenesis; Liver hypertrophy