title: Evaluation of the repeated-dose liver, bone marrow and peripheral blood micronucleus and comet assays using kojic acid.
abstract: The repeated-dose liver micronucleus assay has the potential to detect liver carcinogens and could be integrated into general toxicological studies. To assess the performance of this assay, kojic acid was tested in 14-day and 28-day liver micronucleus assays. We evaluated the incidence of micronucleated cells in liver, bone marrow and peripheral blood and performed comet assays in both the liver and peripheral blood (comet assay was performed only for 14-days). Kojic acid, a skin-whitening agent used in cosmetic products, was orally dosed in six-week-old male rats at 250, 500 and 1000mg/kg/day for 14 days, and at 125, 250 and 500mg/kg/day for 28 days. Organ weight and histopathology were examined at the end of the experiment. Neither a clear, positive response in micronucleus (MN) incidence nor changes in the percent of tail DNA in the comet assays was noted in liver and bone marrow. An increase of relative liver weight was observed in 1000mg/kg/day for 14 days. In histopathology, minimal hypertrophy of hepatocytes was found at 1000mg/kg/day for 14 days. The results of both the micronucleus assay and the comet assay indicate that 14-day and 28-day repeated dosing of kojic acid are non-genotoxic in the liver and bone marrow. Kojic acid has been known to act as a tumor-promoter in thyroid carcinogenesis but has not been shown to have initiation activities in liver carcinogenesis. Findings in this study are consistent with the evidence that kojic acid is not an apparent initiator of liver carcinogenesis. Therefore, the liver micronucleus assay is simple and sensitive to detect genotoxic liver carcinogens.
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan. Electronic address: y-ogiwara@so.taisho.co.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ogiwara
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Sugiura
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tawara
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Endo
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Matsue
authors.affiliation: Drug Safety, Taisho Pharmaceutical, Co., Ltd., 1-403, Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Hisaharu
authors.initials: H
authors.lastname: Yamada
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Wako
authors.affiliation: LSI Medience Corporation, 14-1 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kawasako
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D020552:Comet Assay; D003299:Cooperative Behavior; D004334:Drug Administration Schedule; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007564:Japan; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D015162:Micronucleus Tests; D009183:Mycotoxins / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012957:Societies, Pharmaceutical
chemical_list: D009183:Mycotoxins; D011753:Pyrones; C011890:kojic acid
keywords: Comet assay; Genotoxicity; Kojic acid; Liver; Micronucleus assay