title: Induction of cell proliferation in the rat liver by the short-term administration of ethyl tertiary-butyl ether.
abstract: In the present study, in continuation of our previous experiment in order to investigate the mode of action (MOA) of ethyl tertiary-butyl ether (ETBE) hepatotumorigenicity in rats, we aimed to examine alterations in cell proliferation, that are induced by short-term administration of ETBE. F344 rats were administered ETBE at doses of 0, and 1,000 mg/kg body weight twice a day by gavage for 3, 10, 17 and 28 days. It was found that the previously observed significant increase of P450 total content and hydroxyl radical levels after 7 days of ETBE administration, and 8-OHdG formation at day 14, accompanied by accumulation of CYP2B1/2B2, CYP3A1/3A2, CYP2C6, CYP2E1 and CYP1A1 and downregulation of DNA oxoguanine glycosylase 1, was preceded by induction of cell proliferation at day 3. Furthermore, we observed an increase in regenerative cell proliferation as a result of ETBE treatment at day 28, followed by induction of cell cycle arrest and apoptosis by day 14. These results indicated that short-term administration of ETBE led to a significant early increase in cell proliferation activity associated with induction of oxidative stress, and to a regenerative cell proliferation as an adaptive response, which could contribute to the hepatotumorigenicity of ETBE in rats.
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.affiliation: DIMS Institute of Medical Science, Inc., 64 Goura, Nishiazai, Azai-cho, Ichinomiya, Aichi 491-0113, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hagiwara
authors.affiliation: DIMS Institute of Medical Science, Inc., 64 Goura, Nishiazai, Azai-cho, Ichinomiya, Aichi 491-0113, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Imai
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan ; Japan Bioassay Research Center, Japan Industrial Safety and Health Association, 2445 Hirasawa, Hadano, Kanagawa 257-0011, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
keywords: cell proliferation; ethyl tertiary-butyl ether; mode of action; oxidative stress