Okuda Yu, Kushida Masahiko, Kikumoto Hiroko, Nakamura Yoshimasa, Higuchi Hashihiro, Kawamura Satoshi, Cohen Samuel M, Lake Brian G, Yamada Tomoya
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd.
Graduate School of Environmental and Life Science, Okayama University.
J Toxicol Sci. 2017;42(6):773-788. doi: 10.2131/jts.42.773.
High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 µM) and a major metabolite Z-CMCA (5-1,000 µM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative DNA synthesis in rat and human hepatocytes. However, while NaPB and momfluorothrin increased replicative DNA synthesis in rat hepatocytes, NaPB, momfluorothrin and Z-CMCA did not increase replicative DNA synthesis in human hepatocytes. NaPB, momfluorothrin and Z-CMCA increased CYP2B1/2 mRNA levels in rat hepatocytes. NaPB and momfluorothrin also increased CYP2B6 mRNA levels in human hepatocytes. Overall, while momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative DNA synthesis was not increased in human hepatocytes of chimeric mice treated with momfluorothrin or its close structural analogue metofluthrin. As human hepatocytes are refractory to the mitogenic effects of momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for momfluorothrin-induced rat liver tumor formation is not relevant for humans.
高膳食水平的非基因毒性合成拟除虫菊酯甲氧氟氯菊酯增加了雄性和雌性Wistar大鼠肝细胞肿瘤的发生率。机制研究表明，甲氧氟氯菊酯诱导肝细胞肿瘤的作用模式（MOA）是由组成型雄烷受体（CAR）介导的。在本研究中，为了评估甲氧氟氯菊酯对人类的潜在致癌风险，研究了甲氧氟氯菊酯（1 - 1000 μM）及其主要代谢物Z - CMCA（5 - 1000 μM）对培养的大鼠和人肝细胞制剂中肝细胞复制性DNA合成和CYP2B mRNA表达的影响。还研究了苯巴比妥钠（NaPB）的作用，它是一种具有CAR介导的MOA的典型啮齿动物致癌物。人肝细胞生长因子（hHGF）在大鼠和人肝细胞中引起复制性DNA合成的浓度依赖性增加。然而，虽然NaPB和甲氧氟氯菊酯增加了大鼠肝细胞中的复制性DNA合成，但NaPB、甲氧氟氯菊酯和Z - CMCA并未增加人肝细胞中的复制性DNA合成。NaPB、甲氧氟氯菊酯和Z - CMCA增加了大鼠肝细胞中CYP2B1/2 mRNA水平。NaPB和甲氧氟氯菊酯也增加了人肝细胞中CYP2B6 mRNA水平。总体而言，虽然甲氧氟氯菊酯和NaPB在培养的人肝细胞中激活了CAR，但这两种化学物质均未增加复制性DNA合成。此外，为了确认体外观察到的结果在体内是否也能观察到，进行了一项人源化嵌合小鼠研究。用甲氧氟氯菊酯或其结构类似物甲氧苄氟菊酯处理的嵌合小鼠的人肝细胞中，复制性DNA合成并未增加。与大鼠肝细胞不同，人肝细胞对甲氧氟氯菊酯的促有丝分裂作用不敏感，这些数据支持了甲氧氟氯菊酯诱导大鼠肝脏肿瘤形成的MOA与人类无关这一假说。
