Role of Metabolism and DNA Adduct Formation in the Induction of Sister Chromatid Exchanges in Human Lymphocytes by Diethylstilbestrol1

Recent studies have shown that diethylstilbestrol (DES) induces sister chromatid exchanges (SCEs) in lymphocytes from pregnant and premenopausal women but has only a slight effect on lymphocytes from postmenopausal women or men. In this study blood specimens from premenopausal women were used to define the role of different metabolic pathways on DES-induced formation of SCEs and to determine whether conditions resulting in induction of SCEs also induced detectable levels of DNA adducts. Exposure of lymphocytes in vitro to 0-40 /IM DES induced a concentration-dependent increase in SCEs. Addition of indomethacin to the cultures partially abolished DES-induced SCEs, sug gesting involvement of prostaglandin synthetases in the formation of specific DES metabolites that cause SCEs. a-Naphthoflavone, an inhib itor of cytochrome P-450 monooxygenases, had no effect on DES-induced SCEs. Cells exposed to DES at doses sufficient to cause large increases in SCE induction did not have adducts detectable by a "P-postlabeling assay capable of revealing adducts at a level of 1 adduct/10' normal