Tamoxifen-induced adduct formation and cell stress in human endometrial glands. Drug Metab. Dispos

The beneficial effects of tamoxifen in the prevention and treatment of breast cancer are compromised by an increased risk of endometrial polyps, hyperplasia, and cancer. Tamoxifen ismetabolized to an array of metabolites with estrogenic effects but also to reactive intermedi-ates that may form protein and DNA adducts. The aim of this study was to investigate cellular [3H]tamoxifen adduct formation by light microscopic autoradiography and cell stress by immunohistochemi-cal analysis of glucose-regulating protein 78 (GRP78), nuclear factor B (NF-B), and caspase 3 in human endometrial explants after short-term incubation with tamoxifen. The cellular expression of tamoxifen-metabolizing enzymes in human endometrial biopsy samples was also determined by immunohistochemistry. The results showed se-lective [3H]tamoxifen adduct formation in glandular and surface epi-thelia after incubation with a nontoxic concentration of [3H]tamoxifen (6 nM). There was also a selective expression of the endoplasmi