Mode of action analysis for induction of mouse lung tumors by permethrin: Involvement of CYP2F2 enzyme and human relevancy

Permethrin increases the incidence of bronchiolo-alveolar adenomas in female mice. The proposed mode of action (MOA) for permethrin-induced lung tumorigenesis involves increased mitogenesis in Club cells. Additionally, CYP2F2, which is particularly expressed in mouse lung Club cells and different from human CYP2F1, is considered to be a key factor in mouse-specific lung tumorigenesis. In this study, we investigated the relationship between permethrin-induced mouse lung tumorigenesis and CYP2F2 in CYP2f2 knockout (KO) mice. Fluensulfone and isoniazid were selected as positive controls. We showed that the increased proliferation of Club cells and increased proliferation of smooth endoplasmic reticulum (SER) within them were abolished in permethrin-treated CYP2f2 KO mice, while these changes were clearly observed in permethrin- and positive control-treated wild type mice. Additionally, the disappearance of the Club cell reaction was also observed in positive control-treated CYP2f2 KO mice. Based on these results, it was concluded that CYP2F2 is essential in the MOA of mouse lung tumorigenesis by permethrin, also suggesting that permethrin metabolism by CYP2F2 corresponds to a chain of early key events, including the molecular initiating event (MIE). Furthermore, the data suggested that CYP2F2 played a crucial role in mouse lung tumorigenesis induced by isoniazid, which is known to cause lung tumors in mice but not in humans. The collective data on permethrin-treated mouse lung tumorigenesis, including findings from this study, would lead to the conclusion that the lung tumors induced by permethrin treatment are mouse-specific and not relevant to human lung cancer risk.