Constitutive active/androstane receptor, peroxisome proliferator-activated receptor α, and cytotoxicity are involved in oxadiazon-induced liver tumor development in mice.

Abstract

Oxadiazon (OX) is a protoporphyrinogen oxidase-inhibiting herbicide that induces porphyria and liver tumors in rodents. Although porphyria is generally considered to be a risk factor for liver tumor development, the mechanisms through which OX mediates tumor development are unclear. Therefore, in this study, we investigated the mechanisms of tumor development by focusing on constitutive active/androstane receptor (CAR), which is essential for the development of tumors in response to several chemicals. After 1, 4, or 13 weeks of dietary treatment with 1000 ppm OX, hepatic Cyp2b10 expression was induced in wild-type (WT) mice. However, this effect was blocked in CAR-knockout (CARKO) mice. Hepatic Cyp4a10 expression, indicative of peroxisome proliferator-activated receptor α (PPARα) activation, and cytotoxic changes in hepatocytes were also observed in both groups of mice. After initiation by diethylnitrosamine, 26-week treatment with OX resulted in an increase in proliferative lesions, including foci and adenomas, in both genotypes, and the incidence and multiplicity of proliferative lesions in CARKO mice were higher than those in control mice but lower than those in WT mice. These results suggested that CAR, PPARα activation, and cytotoxicity were involved in the development of liver tumors. Moreover, porphyrin was not apparently involved in OX-induced tumor development.

• Authors: Kazunori Kuwata, Kaoru Inoue, Ryohei Ichimura, Miwa Takahashi, Yukio Kodama, Midori Yoshida
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 88 Pg. 75-86 (Feb 2016) ISSN: 1873-6351 [Electronic] England
• PMID: 26710982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Constitutive Androstane Receptor
• Herbicides
• Oxadiazoles
• PPAR alpha
• Receptors, Cytoplasmic and Nuclear
• oxadiazon

Topics

• Animals
• Carcinogenesis (chemically induced)
• Cell Death
• Cells, Cultured
• Constitutive Androstane Receptor
• Hepatocytes (drug effects)
• Herbicides (toxicity)
• Liver Neoplasms (chemically induced)
• Male
• Mice
• Oxadiazoles (toxicity)
• PPAR alpha (genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (genetics, metabolism)