Deguchi Yoshihito, Yamada Tomoya, Hirose Yukihiro, Nagahori Hirohisa, Kushida Masahiko, Sumida Kayo, Sukata Tokuo, Tomigahara Yoshitaka, Nishioka Kazuhiko, Uwagawa Satoshi, Kawamura Satoshi, Okuno Yasuyoshi
Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka 554-8558, Japan.
Toxicol Sci. 2009 Mar;108(1):69-80. doi: 10.1093/toxsci/kfp006. Epub 2009 Jan 27.
Two-year treatment with high doses of Metofluthrin produced hepatocellular tumors in both sexes of Wistar rats. To understand the mode of action (MOA) by which the tumors are produced, a series of studies examined the effects of Metofluthrin on hepatic microsomal cytochrome P450 (CYP) content, hepatocellular proliferation, hepatic gap junctional intercellular communication (GJIC), oxidative stress and apoptosis was conducted after one or two weeks of treatment. The global gene expression profile indicated that most genes with upregulated expression with Metofluthrin were metabolic enzymes that were also upregulated with phenobarbital. Metofluthrin induced CYP2B and increased liver weights associated with centrilobular hepatocyte hypertrophy (increased smooth endoplasmic reticulum [SER]), and induction of increased hepatocellular DNA replication. CYP2B1 mRNA induction by Metofluthrin was not observed in CAR knockdown rat hepatocytes using the RNA interference technique, demonstrating that Metofluthrin induces CYP2B1 through CAR activation. Metofluthrin also suppressed hepatic GJIC and induced oxidative stress and increased antioxidant enzymes, but showed no alteration in apoptosis. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. All of these effects were reversible upon cessation of treatment. Metofluthrin did not cause cytotoxicity or peroxisome proliferation. Thus, it is highly likely that the MOA for Metofluthrin-induced liver tumors in rats is through CYP induction and increased hepatocyte proliferation, similar to that seen for phenobarbital. Based on analysis with the International Life Sciences Institute/Risk Science Institute MOA framework, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans, at least at expected levels of exposure.
高剂量甲氧氟氯菊酯对Wistar大鼠进行两年治疗后，雌雄大鼠均出现肝细胞肿瘤。为了解肿瘤产生的作用模式（MOA），在治疗1周或2周后，进行了一系列研究，检测甲氧氟氯菊酯对肝微粒体细胞色素P450（CYP）含量、肝细胞增殖、肝间隙连接细胞间通讯（GJIC）、氧化应激和细胞凋亡的影响。整体基因表达谱表明，大多数因甲氧氟氯菊酯而上调表达的基因是代谢酶，这些酶也会因苯巴比妥而上调。甲氧氟氯菊酯诱导CYP2B并增加肝脏重量，伴有小叶中央肝细胞肥大（滑面内质网[SER]增加），并诱导肝细胞DNA复制增加。使用RNA干扰技术在CAR基因敲低的大鼠肝细胞中未观察到甲氧氟氯菊酯对CYP2B1 mRNA的诱导作用，表明甲氧氟氯菊酯通过激活CAR诱导CYP2B1。甲氧氟氯菊酯还抑制肝GJIC，诱导氧化应激并增加抗氧化酶，但未显示细胞凋亡有改变。在致癌剂量水平或以下观察到上述与甲氧氟氯菊酯诱导肝肿瘤关键事件相关的参数。停止治疗后，所有这些影响都是可逆的。甲氧氟氯菊酯不会引起细胞毒性或过氧化物酶体增殖。因此，甲氧氟氯菊酯在大鼠中诱导肝肿瘤的作用模式很可能是通过诱导CYP和增加肝细胞增殖，类似于苯巴比妥的情况。根据国际生命科学研究所/风险科学研究所作用模式框架的分析，合理的结论是，至少在预期暴露水平下，甲氧氟氯菊酯对人类不会有任何致癌活性。
