title: Structural and numerical chromosome aberration inducers in liver micronucleus test in rats with partial hepatectomy.
abstract: The liver micronucleus test is an important method to detect pro-mutagens such as active metabolites not reaching bone marrow due to their short lifespan. We have already reported that dosing of the test compound after partial hepatectomy (PH) is essential to detect genotoxicity of numerical chromosome aberration inducers in mice [Mutat. Res. 632 (2007) 89-98]. In naive animals, the proportion of binucleated cells in rats is less than half of that in mice, which suggests a species difference in the response to chromosome aberration inducers. In the present study, we investigated the responses to structural and numerical chromosome aberration inducers in the rat liver micronucleus test. Two structural chromosome aberretion inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used in the present study. PH was performed a day before or after the dosing of the test compound in 8-week old male F344 rats and hepatocytes were isolated 4 days after the PH. As a result, diethylnitrosamine and 1,2-dimethylhydrazine, structural chromosome aberration inducers, exhibited significant increase in the incidence of micronucleated hepatocyte (MNH) when given either before and after PH. Colchicine and carbendazim, numerical chromosome aberration inducers, did not result in any toxicologically significant increase in MNH frequency when given before PH, while they exhibited MNH induction when given after PH. It is confirmed that dosing after PH is essential in order to detect genotoxicity of numerical chromosome aberration inducers in rats as well as in mice. Regarding the species difference, a different temporal response to colchicine was identified. Colchicine increased the incidence of MNH 4 days after PH in rats, although such induction in mice was observed 8-10 days after PH.
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Horikoshi 717, Fukuroi-shi, Shizuoka-ken 437-0065 Japan. Electronic address: itoh.satoru.n5@daiichisankyo.co.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Itoh
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Horikoshi 717, Fukuroi-shi, Shizuoka-ken 437-0065 Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Hattori
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Horikoshi 717, Fukuroi-shi, Shizuoka-ken 437-0065 Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nagata
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Horikoshi 717, Fukuroi-shi, Shizuoka-ken 437-0065 Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
mesh_terms: D024422:Aneugens / Q000633:toxicity*; D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity; D002219:Carbamates / Q000633:toxicity; D002869:Chromosome Aberrations; D003078:Colchicine / Q000031:analogs & derivatives / Q000633:toxicity; D004249:DNA Damage; D004052:Diethylnitrosamine / Q000633:toxicity; D004127:Dimethylhydrazines / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006498:Hepatectomy; D008099:Liver; D008297:Male; D015162:Micronucleus Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D024422:Aneugens; D001562:Benzimidazoles; D002219:Carbamates; D004127:Dimethylhydrazines; D009153:Mutagens; D004052:Diethylnitrosamine; C006698:carbendazim; C012852:colchiceine; D003078:Colchicine