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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.
AuthorsAnna Kakehashi, Akihiro Hagiwara, Norio Imai, Min Wei, Shoji Fukushima, Hideki Wanibuchi
JournalJournal of toxicologic pathology (J Toxicol Pathol) Vol. 28 Issue 1 Pg. 27-32 (Jan 2015) ISSN: 0914-9198 [Print] Japan
PMID26023258 (Publication Type: Journal Article)

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