There is no direct evidence that tamoxifen is active in tests for gene mutation. Preliminary studies indicate that tamoxifen does not give rise to detectable levels of DNA adducts in human liver in vivo or in human endometrium in vitro and in vivo . Mechanistic considerations Tamoxifen increases liver tumour incidence in rats, which may involve both DNA damage leading to increased numbers of initiated cells and oestrogen receptor-mediated clonal expansion of those initiated cells. The available evidence suggests that tamoxifen is carcinogenic in rat liver by a genotoxic mechanism. Preliminary information from studies of human tissues suggests that humans are less susceptible to the genotoxicity of tamoxifen.
Tamoxifen also possesses tumour-promoting activity in the rat liver.
Several studies have shown that the liver contains significant quantities of oestrogen receptor in hepatocytes, Kupffer cells and endothelial cells. In some tissues, such as breast, tamoxifen exhibits antioestrogenic properties by binding to the oestrogen receptor with high affinity. Thus, oestrogen receptor binding does not result in normal transcriptional activity. In other tissues, such as bone and liver, tamoxifen acts as a partial agonist, possibly because cells from those tissues contain a different array of DNA binding sites, thereby leading to typical oestrogen-mediated changes in gene expression and subsequent biological effects on growth and differentiation. There is sufficient evidence in humans for the carcinogenicity of tamoxifen in increasing the risk for endometrial cancer and there is conclusive evidence that tamoxifen reduces the risk for contralateral breast cancer in women with a previous diagnosis of breast cancer.