title: Involvement of constitutive androstane receptor in liver hypertrophy and liver tumor development induced by triazole fungicides.
abstract: We clarified the involvement of constitutive androstane receptor (CAR) in triazole-induced liver hypertrophy and tumorigenesis using CAR-knockout (CARKO) mice. Seven-week-old male CARKO and wild-type (WT) mice were treated with 200 ppm cyproconazole (Cypro), 1500 ppm tebuconazole (Teb), or 200 ppm fluconazole (Flu) in the diet for 27 weeks after initiation by diethylnitrosamine (DEN). At weeks 4 (without DEN) and 13 (with DEN), WT mice in all treatment groups and CARKO mice in Teb group revealed liver hypertrophy with mainly Cyp2b10 and following Cyp3a11 inductions in the liver. Teb also induced Cyp4a10 in both genotypes. Cypro induced slight and duration-dependent liver hypertrophy in CARKO mice. At week 27, Cypro and Teb significantly increased eosinophilic altered foci and/or adenomas in WT mice. These proliferating lesions were clearly reduced in CARKO mice administered both compounds. The eosinophilic adenomas caused by Flu decreased in CARKO mice. The present study indicates that CAR is the main mediator of liver hypertrophy induced by Cypro and Flu, but not Teb. In contrast, CAR played a crucial role in liver tumor development induced by all three triazoles.
authors: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Kei
authors: K
authors: Tamura
authors: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Kaoru
authors: K
authors: Inoue
authors: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Miwa
authors: M
authors: Takahashi
authors: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Saori
authors: S
authors: Matsuo
authors: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Kaoru
authors: K
authors: Irie
authors: Division of Toxicology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
authors: Yukio
authors: Y
authors: Kodama
authors: Department of Pharmacodynamics Molecular Genetics, School of Pharmacy, Iwate Medical University, Shiwa-Gun, Iwate 020-8505, Japan.
authors: Toshie
authors: T
authors: Gamo
authors: Department of Pharmacodynamics Molecular Genetics, School of Pharmacy, Iwate Medical University, Shiwa-Gun, Iwate 020-8505, Japan.
authors: Shogo
authors: S
authors: Ozawa
authors: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan. Electronic address: midoriy@nihs.go.jp.
authors: Midori
authors: M
authors: Yoshida
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004052:Diethylnitrosamine / Q000633:toxicity; D015725:Fluconazole / Q000633:toxicity*; D005659:Fungicides, Industrial / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006529:Hepatomegaly / Q000139:chemically induced / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000633:toxicity*
chemical_list: D000090702:Constitutive Androstane Receptor; D005659:Fungicides, Industrial; D008565:Membrane Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D004052:Diethylnitrosamine; C087114:tebuconazole; C093628:cyproconazole; D015725:Fluconazole; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D000410:Alanine Transaminase
keywords: CAR; Cyp2b; Liver hypertrophy; Liver tumorigenesis; Mice; Triazoles