Kuwata Kazunori, Inoue Kaoru, Ichimura Ryohei, Takahashi Miwa, Kodama Yukio, Yoshida Midori
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.
Division of Pathology, National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan.
Food Chem Toxicol. 2016 Feb;88:75-86. doi: 10.1016/j.fct.2015.12.017. Epub 2015 Dec 19.
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.
恶草酮（OX）是一种抑制原卟啉原氧化酶的除草剂，可在啮齿动物中诱发卟啉症和肝肿瘤。尽管卟啉症通常被认为是肝肿瘤发生的一个风险因素，但OX介导肿瘤发生的机制尚不清楚。因此，在本研究中，我们聚焦于组成型活性/雄甾烷受体（CAR）来研究肿瘤发生的机制，CAR对于响应多种化学物质而发生的肿瘤发展至关重要。在用1000 ppm OX进行饮食处理1、4或13周后，野生型（WT）小鼠肝脏中的Cyp2b10表达被诱导。然而，在CAR基因敲除（CARKO）小鼠中这种效应被阻断。两组小鼠均观察到肝脏Cyp4a10表达（指示过氧化物酶体增殖物激活受体α（PPARα）激活）以及肝细胞的细胞毒性变化。在用二乙基亚硝胺启动后，用OX进行26周的处理导致两种基因型的增殖性病变（包括灶性病变和腺瘤）均增加，并且CARKO小鼠中增殖性病变的发生率和多发性高于对照小鼠，但低于WT小鼠。这些结果表明，CAR、PPARα激活和细胞毒性参与了肝肿瘤的发生。此外，卟啉显然未参与OX诱导的肿瘤发生。
