title: Evaluation of the genotoxicity of tamoxifen in the liver and kidney of F344 gpt delta transgenic rat in 3-week and 13-week repeated dose studies.
abstract: Transgenic rat gene mutation assays can be used to assess genotoxicity of chemicals in target organs for carcinogenicity. Mutations in transgenes are genetically neutral and accumulate during a treatment period; thus, the assays are suitable for assessment of the genotoxicity risk of chemicals using a repeated-dose treatment paradigm. However, few such studies have been conducted. To examine the utility of the transgenic rat assays in repeated-dose studies, we treated female F344 gpt delta rats with tamoxifen (TAM) at 20 and 40mg/kg, or toremifene (TOR) at 40mg/kg by gavage daily for 3 weeks. We also fed gpt delta rats with TAM at either 250ppm (15.4-17.6mg/kg) or 500ppm (30.0-32.9mg/kg) for 13 weeks. TAM is carcinogenic in the rat liver and TOR is not carcinogenic. TAM administration significantly increased gpt (point mutations) and Spi(-) (deletions) mutant frequencies (MFs) in the liver, the target organ of carcinogenesis; MFs were higher after treatment for 13 weeks than after treatment for 3 weeks. The MFs in the kidney did not increase in any of the TAM treatment groups. TOR had no effect on MFs (gpt and Spi(-)) in either the liver or the kidney. We conclude that the gpt delta rat assay in the repeated-dose treatment paradigm is sensitive enough to detect gene mutations induced by TAM in the target organ for carcinogenesis. Furthermore, the assay can be integrated into a 13-week dose-finding study for a 2-year cancer bioassay.
authors.affiliation: Toxicology Laboratory, Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. Electronic address: yuuji.kawamura@meiji.com.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kurata
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hiratsuka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Masumura
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D029968:Escherichia coli Proteins / Q000235:genetics*; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D009152:Mutagenicity Tests / Q000379:methods*; D010430:Pentosyltransferases / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D013629:Tamoxifen / Q000633:toxicity*; D017312:Toremifene / Q000633:toxicity
chemical_list: D029968:Escherichia coli Proteins; D013629:Tamoxifen; D017312:Toremifene; D010430:Pentosyltransferases; C071962:Gpt protein, E coli
keywords: F344 gpt delta transgenic rat; Repeated-dose studies; Spi(−) assay; Tamoxifen; Toremifene; gpt assay