Involvement of constitutive androstane receptor in liver hypertrophy and liver tumor development induced by triazole fungicides

• Published in: Food and chemical toxicology 2015-04, Vol.78, p.86-95
• Main Authors: Tamura, Kei, Inoue, Kaoru, Takahashi, Miwa, Matsuo, Saori, Irie, Kaoru, Kodama, Yukio, Gamo, Toshie, Ozawa, Shogo, Yoshida, Midori
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - blood; Animals; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; CAR; Cell Proliferation - drug effects; Cyp2b; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Cytochrome P450 Family 2; Diethylnitrosamine - toxicity; Fluconazole - toxicity; Fungicides, Industrial - toxicity; Hepatocytes - drug effects; Hepatocytes - pathology; Hepatomegaly - chemically induced; Hepatomegaly - pathology; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver hypertrophy; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - pathology; Liver tumorigenesis; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C3H; Mice, Knockout; Organ Size - drug effects; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Triazoles; Triazoles - toxicity
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2015.01.021

•We clarify the involvement of CAR in triazole-induced liver hypertrophy and tumors.•Cyproconazole and fluconazole induced liver hypertrophy mediated primarily by CAR.•Tebuconazole induced severe liver hypertrophy similar to WT and CARKO mice.•CAR played a crucial role in hepatocarcinogenesis induced by all 3 triazoles.•Liver hypertrophy is an associative event involved in CAR-mediated liver tumor promotion in rodents. 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.