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Food Chem Toxicol. 2015 Apr;78:86-95. doi: 10.1016/j.fct.2015.01.021. Epub 2015 Feb 2.

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

Author information

1
Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
2
Division of Toxicology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
3
Department of Pharmacodynamics Molecular Genetics, School of Pharmacy, Iwate Medical University, Shiwa-Gun, Iwate 020-8505, Japan.
4
Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan. Electronic address: midoriy@nihs.go.jp.

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.

KEYWORDS:

CAR; Cyp2b; Liver hypertrophy; Liver tumorigenesis; Mice; Triazoles

PMID:
25656644
DOI:
10.1016/j.fct.2015.01.021
[Indexed for MEDLINE]

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