A crucial role of constitutive androstane receptor (CAR) in liver tumor development by imazalil in mice

• Published in: Journal of toxicological sciences Vol. 41; no. 6; pp. 801 - 811
• Main Authors: Tamura, Kei, Inoue, Kaoru, Takahashi, Miwa, Matsuo, Saori, Kodama, Yukio, Yoshida, Midori
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2016; Japan Science and Technology Agency
• Subjects: Adenoma - chemically induced; Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Animals; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; CAR; Carcinogens; Cars; Cell Proliferation - drug effects; Cocarcinogenesis; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Cytochrome P450 Family 2 - genetics; Cytochrome P450 Family 2 - metabolism; Diethylnitrosamine; Diethylnitrosamine - toxicity; Dose-Response Relationship, Drug; Enzymes; Fungicides; Fungicides, Industrial - toxicity; Genotype; Genotypes; Hypertrophy; Imazalil; Imidazole; Imidazoles - toxicity; Leukocytes (eosinophilic); Liver; Liver hypertrophy; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Liver tumorigenesis; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C3H; Mice, Knockout; Phenotype; Receptors, Cytoplasmic and Nuclear - deficiency; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Risk Assessment; Rodents; Signal Transduction - drug effects; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Time Factors; Toxicology; Tumors
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.41.801

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.