title: Genotoxicity of phenacetin in the kidney and liver of Sprague-Dawley gpt delta transgenic rats in 26-week and 52-week repeated-dose studies.
abstract: Transgenic rat mutation assays can be used to assess genotoxic properties of chemicals in target organs for carcinogenicity. Mutations in transgenes are genetically neutral and accumulate during a treatment period; thus, assays are suitable for assessing the genotoxic risk of chemicals using a repeated-dose treatment paradigm. However, only a limited number of such studies have been conducted. To examine the utility of transgenic rat assays in repeated-dose studies, we fed male and female Sprague-Dawley gpt delta rats with a 0.5% phenacetin-containing diet for 26 and 52 weeks. A long-term feeding of phenacetin is known to induce renal cancer in rats. Phenacetin administration for 52 weeks in males significantly increased gpt (point mutations) mutant frequency (MF) in the kidney, the target organ of carcinogenesis. In the liver, the nontarget organ of carcinogenesis, gpt MFs were significantly elevated in phenacetin treatment groups of both genders during 26- and 52-week treatments. Furthermore, sensitive to P2 interference (Spi(-)deletions) MF increased in the liver of both genders following 52-week treatment. MFs were higher after treatment for 52 weeks than after treatment for 26 weeks. Frequencies of phenacetin-induced mutations were higher in the liver than in the kidney, suggesting that the intensity of genotoxicity does not necessarily correlate with the induction of tumor formation. Results from gpt delta rat assays of repeated-dose treatments are extremely useful to elucidate the relationship between gene mutations and carcinogenesis in the target organ induced by cancer-causing agents.
authors.affiliation: Toxicology Laboratory, Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd. 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan; Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. Electronic address: yuuji.kawamura@meiji.com.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Research Planning & Management, R&D Planning & Management Department, Meiji Seika Pharma Co., Ltd. 2-4-16 Kyobashi, Chuo-ku, Tokyo 104-8002, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Masumura
authors.affiliation: Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Numazawa
authors.affiliation: Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009152:Mutagenicity Tests; D010615:Phenacetin / Q000633:toxicity*; D017354:Point Mutation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D007041:Hypoxanthine Phosphoribosyltransferase; D010615:Phenacetin
keywords: Phenacetin; Renal tumor; Repeated-dose study; Spi(–)assay; Target organ; gpt assay; gpt delta transgenic rat