Editor's Highlight: Mode of Action Analysis for Rat Hepatocellular Tumors Produced by the Synthetic Pyrethroid Momfluorothrin: Evidence for Activation of the Constitutive Androstane Receptor and Mitogenicity in Rat Hepatocytes

Toxicological Sciences : an Official Journal of the Society of Toxicology
Yu OkudaTomoya Yamada

Abstract

High dietary levels of momfluorothrin, a nongenotoxic synthetic pyrethroid, induced hepatocellular tumors in male and female Wistar rats in a 2-year bioassay. The mode of action (MOA) for rat hepatocellular tumors was postulated to occur via activation of the constitutive androstane receptor (CAR), as momfluorothrin is a close structural analogue of the pyrethroid metofluthrin, which is known to produce rat liver tumors through a CAR-mediated MOA. To elucidate the MOA for rat hepatocellular tumor formation by momfluorothrin, this study was conducted to examine effects on key and associative events of the CAR-mediated MOA for phenobarbital based on the International Programme on Chemical Safety framework. A 2-week in vivo study in Wistar rats revealed that momfluorothrin induced CYP2B activities, increased liver weights, produced hepatocyte hypertrophy and increased hepatocyte replicative DNA synthesis. These effects correlated with the dose-response relationship for liver tumor formation and also showed reversibility upon cessation of treatment. Moreover, momfluorothrin did not increase CYP2B1/2 mRNA expression and hepatocyte replicative DNA synthesis in CAR knockout rats. Using cultured Wistar rat hepatocytes and the RNA inter...Continue Reading

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Citations

Jan 11, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Miwa KondoTomoya Yamada
May 16, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Bryan MackowiakHongbing Wang
Apr 25, 2018·Critical Reviews in Toxicology·Paolo Boffetta, Vimi Desai
Feb 3, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Sarah Da Won BaeJacob George

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