title: 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.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan; Safety Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1-1-1, Kazusakamatari, Kisarazu, Chiba 292-0818, Japan; Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kuwata
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ichimura
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Toxicology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan; Food Safety Commission, Cabinet Office, Akasaka Park Bld 22F, 5-2-20 Akasaka, Minato-ku, Tokyo 107-6122, Japan. Electronic address: midori.yoshida@cao.go.jp.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced; D016923:Cell Death; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D022781:Hepatocytes / Q000187:drug effects; D006540:Herbicides / Q000633:toxicity; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000633:toxicity*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; D006540:Herbicides; D010069:Oxadiazoles; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; C012466:oxadiazon
keywords: CAR; Liver tumorigenesis; Mice; Oxadiazon; Porphyrin