Tamoxifen is a non-steroidal anti-estrogenic drug widely used for the treatment and prevention of
breast cancer in women; however, there is evidence that
tamoxifen is hepatocarcinogenic in rats, but not in mice. Additionally, it has been reported that
tamoxifen may cause
non-alcoholic fatty liver disease (
NAFLD) in humans and experimental animals. The goals of the present study were to (i) investigate the mechanisms of the resistance of mice to
tamoxifen-induced hepatocarcinogenesis, and (ii) clarify effects of
tamoxifen on
NAFLD-associated liver injury. Feeding female WSB/EiJ mice a 420 p.p.m.
tamoxifen-containing diet for 12 weeks resulted in an accumulation of
tamoxifen-
DNA adducts, (E)-α-(deoxyguanosin-N(2)-yl)-tamoxifen (dG-TAM) and (E)-α-(deoxyguanosin-N(2)-yl)-N-desmethyltamoxifen (dG-DesMeTAM), in the livers. The levels of hepatic dG-TAM and dG-DesMeTAM
DNA adducts in
tamoxifen-treated mice were 578 and 340 adducts/108
nucleotides, respectively, while the extent of global
DNA and repetitive elements methylation and histone modifications did not differ from the values in control mice. Additionally, there was no biochemical or histopathological evidence of
NAFLD-associated liver injury in mice treated with
tamoxifen. A transcriptomic analysis of differentially expressed genes demonstrated that
tamoxifen caused predominantly down-regulation of hepatic lipid metabolism genes accompanied by a distinct over-expression of the
lipocalin 13 (Lcn13) and peroxisome proliferator receptor gamma (Pparγ), which may prevent the development of
NAFLD. The results of the present study demonstrate that the resistance of mice to
tamoxifen-induced liver
carcinogenesis may be associated with its ability to induce genotoxic alterations only without affecting the cellular epigenome and an inability of
tamoxifen to induce the development of
NAFLD.