Journal Article

Mode of Action Analysis for the Synthetic Pyrethroid Metofluthrin-Induced Rat Liver Tumors: Evidence for Hepatic CYP2B Induction and Hepatocyte Proliferation

Yoshihito Deguchi, Tomoya Yamada, Yukihiro Hirose, Hirohisa Nagahori, Masahiko Kushida, Kayo Sumida, Tokuo Sukata, Yoshitaka Tomigahara, Kazuhiko Nishioka, Satoshi Uwagawa, Satoshi Kawamura and Yasuyoshi Okuno

in Toxicological Sciences

Volume 108, issue 1, pages 69-80
Published in print March 2009 | ISSN: 1096-6080
Published online January 2009 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfp006
Mode of Action Analysis for the Synthetic Pyrethroid Metofluthrin-Induced Rat Liver Tumors: Evidence for Hepatic CYP2B Induction and Hepatocyte Proliferation

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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.

Keywords: hepatocarcinogenesis; constitutive androstane receptor (CAR); phenobarbital; nongenotoxic; RNA interference (RNAi); toxicogenomics

Journal Article.  8163 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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