title: A crucial role of constitutive androstane receptor (CAR) in liver tumor development by imazalil in mice.
abstract: To clarify the major pathway of liver tumor development induced by imazalil (IMA), an imidazole fungicide, male constitutive androstane receptor (CAR)-knockout (CARKO) and wild-type (WT) mice were treated with IMA at 500 ppm in the diet up to 27 weeks after initiation by diethylnitrosamine. After 27 weeks of treatment, neither altered foci nor adenomas were significantly increased in CARKO mice, whereas both eosinophilic altered foci and adenomas were increased in WT mice. After 4 or 13 weeks of IMA treatment, liver hypertrophy was observed at the tumor-inducible dose without differences among genotypes or durations. Analysis of hepatic drug metabolite enzymes, performed after administration of multiple doses during a 1-week period, indicated that pregnane X receptor might be involved in liver hypertrophy because IMA markedly elevated Cyp3a11 and Cyp2b10 expression levels in a dose-dependent manner in both genotypes. Our results demonstrated that the CAR pathway was the main mechanism of liver tumor development induced by IMA. The carcinogenic pathway was different from that of liver hypertrophy.
authors.affiliation: Division of Pathology, National Institute of Health Sciences.
authors.forename: Kei
authors.initials: K
authors.lastname: Tamura
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.forename: Saori
authors.initials: S
authors.lastname: Matsuo
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000236:Adenoma / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003043:Cocarcinogenesis; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2 / Q000235:genetics / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000633:toxicity*; D005838:Genotype; D006984:Hypertrophy; D007093:Imidazoles / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D000090702:Constitutive Androstane Receptor; D005659:Fungicides, Industrial; D007093:Imidazoles; D008565:Membrane Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D004052:Diethylnitrosamine; C017435:enilconazole; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2