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Elevated 8-Hydroxydeoxyguanosine Levels in DNA of Diethylstilbestrol-treated Syrian Hamsters: Covalent DNA Damage by Free Radicals Generated by Redox Cycling of Diethylstilbestrol¹

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77550-2782 [D. R., J. G. L.], and Molecular Toxicology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104 [R. A. F.]

The generation of free radicals by microsome-mediated redox cycling between catechol estrogens or diethylstilbestrol and their corresponding quinones has previously been demonstrated in vitro. However, the reaction of free radicals with DNA has not yet been detected in animals treated with estrogen and is the subject of this investigation. The reaction of guanine bases of DNA with hydroxyl radicals to form 8-hydroxydeoxyguanosine has been used as a monitor of free radical generation in kidney and liver of Syrian hamsters, a species prone to estrogen-induced carcinogenesis. Prior to in vivo measurements, the in vitro hydroxylation of guanine bases of DNA under conditions of redox cycling of estrogen was investigated. In incubations of DNA or deoxyguanosine with hamster kidney microsomes, NADPH, and diethylstilbestrol, 4',4''-quinone, the hydroxylation of guanine bases of free deoxyguanosine or of DNA was 50 to 100% higher than in controls. When incubations were carried out in the presence of iron (III) chloride, the hydroxylation of guanine bases was 2.5- or 10-fold higher than control values. There was a 65% increase from control values in levels of 8-hydroxydeoxyguanosine in liver DNA of hamsters treated with 20 mg/kg/day diethylstilbestrol for 3 days and 100 mg/kg on the 4th day. In hamsters treated chronically with diethyl-stilbestrol implants for 15 days, 8-hydroxydeoxyguanosine levels more than doubled from control values in kidney but not liver DNA. Treatment of hamsters with estradiol for various time periods did not induce any changes in levels of hydroxylated guanine in either kidney or liver. It was concluded that in vitro and in vivo redox cycling of diethylstilbestrol hydroxylated guanine bases in DNA.

¹ This work was supported by Grants CA 43233 and CA42854 from the National Cancer Institute, National Institutes of Health.

² To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77550-2782.

Received 12/ 5/91. Accepted 5/17/91.

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