Role of metabolism and DNA adduct formation in the induction of sister chromatid exchanges in human lymphocytes by diethylstilbestrol.
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 post-menopausal 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 microM DES induced a concentration-dependent increase in SCEs. Addition of indomethacin to the cultures partially abolished DES-induced SCEs, suggesting involvement of prostaglandin synthetases in the formation of specific DES metabolites that cause SCEs. alpha-Naphthoflavone, an inhibitor 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 32P-postlabeling assay capable of revealing adducts at a level of 1 adduct/10(9) normal nucleotides.
Lundgren
K
K
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Randerath
K
K
Everson
R B
RB
D001571:Benzoflavones / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000648:ultrastructure; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D001571:Benzoflavones; C011512:alpha-naphthoflavone; D004054:Diethylstilbestrol; D004247:DNA; D007213:Indomethacin