Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5859138 | Toxicology | 2014 | 9 Pages |
Abstract
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-N2-yl)-tamoxifen (dG-TAM) and (E)-α-(deoxyguanosin-N2-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.
Keywords
DNA methyltransferase 1Dnmt1DNMT3BDNA methyltransferase 3BH3K27COL1A1collagen, type I, alpha 1H3K4DNMT3Aα-SMAH3K9DNA methyltransferase 3aS-adenosyl-l-homocysteineNAFLDhistone H3 lysine 27histone H3 lysine 9histone H3 lysine 4SAHGAPDHDNA adductsPPARγALTqRT-PCRSAMS-adenosyl-L-methionineASTalanine transaminaseEpigeneticsα-smooth muscle actinGene expressionnon-alcoholic fatty liver diseasetamoxifenaspartate transaminasequantitative reverse transcription-PCRlactate dehydrogenaseLDHMouseLiverglyceraldehyde-3-phosphate dehydrogenase
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Authors
Aline de Conti, Volodymyr Tryndyak, Mona I. Churchwell, Stepan Melnyk, John R. Latendresse, Levan Muskhelishvili, Frederick A. Beland, Igor P. Pogribny,