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

Epidemiology Branch, Biometry and Risk Assessment Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [K. L., R. B. E.], and Department of Pharmacology, Baylor College of Medicine, Texas Medical Center, Houston, Texas 77030 [K. R.]

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 µM 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. -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/10⁹ normal nucleotides.

¹ This work was supported by USPHS Grant CA 32157 to K. R.

² Present address: Optisk Laboratorium, Lundtoftevej 100, 2800 Lyngby, Denmark.

³ To whom requests for reprints should be addressed. Present address: Chief, Epidemiology Branch, Health Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC 27711.

Received 12/18/86. Revised 10/13/87. Accepted 10/15/87.