The drug
tamoxifen, used to treat
breast cancer, causes
liver cancer in rats and
endometrial cancer in women.
Tamoxifen forms liver
DNA adducts in both short- and long-term dosing of rodents, and
DNA adducts have also been reported in tissues of women undergoing
tamoxifen therapy. It is not known if the induction of
endometrial cancer in women is through these
DNA adducts or through the estrogenic nature of the drug. In this study, we have investigated the mutagenicity of two model reactive intermediates of
tamoxifen,
alpha-acetoxytamoxifen and
4-hydroxytamoxifen quinone methide (4-OHtamQM). These form the same
DNA adducts as those found in
tamoxifen-treated rats. The two compounds were used to treat the pSP189 plasmid containing the supF gene, which was replicated in Ad293 cells before being screened in
indicator bacteria. Plasmid reacted with 4-OHtamQM was more likely to be mutated (2-7-fold increase) than that reacted with
alpha-acetoxytamoxifen, despite having a lower level of DNA damage (12-20-fold less), as assayed by (32)P-postlabeling. The two compounds induced statistically different mutation spectra in the supF gene. The majority of mutations in
alpha-acetoxytamoxifen-treated plasmid were GC -->TA transversions while GC-->AT transitions were formed in 4-OHtamQM-treated plasmid. 4-OHTamQM-treated
DNA induced a larger proportion of multiple mutations and large deletions compared to
alpha-acetoxytamoxifen. Sites of mutational hotspots were observed for both compounds. In conclusion, the quantitatively minor
DNA adduct of
tamoxifen (dG-N(2)-4-hydroxytamoxifen) is more mutagenic than the major
tamoxifen DNA adduct (dG-N(2)-tamoxifen).