Adducts and tamoxifen.

In a variety of organs and cells, multiple types of DNA-adducts have been identified before and after treatment with carcinogens. Evidence has been presented that tamoxifen DNA-adducts in treated rat liver cells are related to its rat liver carcinogenicity. Specific metabolites of tamoxifen have been reported to be proximal carcinogens in rat liver, particularly the alpha-hydroxy tamoxifen and possibly other oxygenated metabolites. Similar analyses of human liver and human endometrium of patients treated with tamoxifen did not provide evidence for the presence of tamoxifen-related metabolites. Some preliminary data suggest that tamoxifen may reduce the background DNA-adducts in some human tissues. Inasmuch as there was no increase in tamoxifen-related adducts in human liver samples from tamoxifen-treated patients, it was not surprising that there is no consistent clinical evidence for tamoxifen-related human liver cancer. The lack of tamoxifen adducts in human endometrium indicates that if tamoxifen is a human endometrial carcinogen (International Agency for Research on Cancer, unpublished observations), its mechanism of carcinogenicity is different from that for rat liver, in which DNA-adduct formation has been readily demonstrated.