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.