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: Kei Tamura, Kaoru Inoue, Miwa Takahashi, Saori Matsuo, Kaoru Irie, Yukio Kodama, Toshie Gamo, Shogo Ozawa, Midori Yoshida
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 78 Pg. 86-95 (Apr 2015) ISSN: 1873-6351 [Electronic] England
• PMID: 25656644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Constitutive Androstane Receptor
• Fungicides, Industrial
• Membrane Proteins
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Triazoles
• Diethylnitrosamine
• tebuconazole
• cyproconazole
• Fluconazole
• Steroid Hydroxylases
• Aryl Hydrocarbon Hydroxylases
• Cyp2b10 protein, mouse
• Cyp3a11 protein, mouse
• Cytochrome P-450 CYP1A2
• Cytochrome P-450 CYP3A
• Cytochrome P450 Family 2
• Mdm2 protein, mouse
• Proto-Oncogene Proteins c-mdm2
• Alanine Transaminase

Topics

• Alanine Transaminase (blood)
• Animals
• Aryl Hydrocarbon Hydroxylases (genetics, metabolism)
• Cell Proliferation (drug effects)
• Constitutive Androstane Receptor
• Cytochrome P-450 CYP1A2 (genetics, metabolism)
• Cytochrome P-450 CYP3A (genetics, metabolism)
• Cytochrome P450 Family 2
• Diethylnitrosamine (toxicity)
• Fluconazole (toxicity)
• Fungicides, Industrial (toxicity)
• Hepatocytes (drug effects, pathology)
• Hepatomegaly (chemically induced, pathology)
• Liver (drug effects, metabolism, pathology)
• Liver Neoplasms, Experimental (chemically induced, pathology)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C3H
• Mice, Knockout
• Organ Size (drug effects)
• Proto-Oncogene Proteins c-mdm2 (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)
• Steroid Hydroxylases (genetics, metabolism)
• Triazoles (toxicity)