This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ratko, T. A. Articles by Beattie, C. W. Search for Related Content PubMed PubMed Citation Articles by Ratko, T. A. Articles by Beattie, C. W.

Estrous Cycle Modification of Rat Mammary Gland DNA Alkylation by N-Methyl-N-nitrosourea¹

Department of Pharmacology [T. A. R., C. W. B.] and Division of Surgical Oncology [R. J. B., J. M. P., C. W. B.], University of Illinois School of Medicine at Chicago; the Veterans Administration West Side and Cook County Hospitals; and the Hektoen Institute for Medical Research, Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago [J. M. P.], Chicago, Illinois 60612

Virgin Sprague-Dawley rats exhibiting regular estrous cycles were used as a model system to determine whether the level of circulating estrogen modifies the alkylation pattern of mammary gland DNA by a direct-acting carcinogen, N-methyl-N-nitrosourea (NMU). The concentration of 7-methylguanine and O⁶-methylguanine were similar in mammary epithelial DNA 0.25, 0.50, and 1.0 h after i.v. injection of 50 mg/kg body weight NMU on different days of the rat estrous cycle. However, O⁶-methylguanine was significantly higher in mammary gland DNA 8 and 24 h after a single i.v. dose of carcinogen on proestrus or estrus, compared to rats receiving carcinogen on diestrus. There was no difference in the 7-methylguanine levels at 8 h in any group, but this adduct was higher in estrous-treated rats at 24 h. The ratio of O⁶-methylguanine to 7-methylguanine was significantly lower at 8 h in mammary gland DNA from diestrous-injected rats, and this difference reflected the lower level of O⁶-methylguanine adducts in this group. In contrast, O⁶-methylguanine concentrations in DNA extracted from the liver of the same animals were virtually identical at all time periods examined. 7-Methylguanine levels were higher in the liver at 0.5, 1, 8, and 24 h post-NMU in proestrus as compared with diestrous-injected rats. The observed adduct clearance suggests that rat mammary epithelium may contain repair systems capable of removing O⁶-methylguanine. These results also suggest that the initial removal of the O⁶-methylguanine lesions in mammary epithelial DNA (rather than the initial rate of alkylation) is affected by the hormonal environment during carcinogen exposure. This effect may be tissue specific since removal of O⁶-methylguanine from liver DNA is apparently not altered by the stage of the estrous cycle at which NMU is administered.

¹ Some of these results were presented at the Seventy-seventh Annual Meeting of the American Association for Cancer Research, Los Angeles, CA, May 7–10, 1986. Supported in part by National Cancer Institute Grant P01 CA31827, the Carol Thomas Brigham Fund, and the Seymour Engel Cancer Research Fund.

² USPHS Predoctoral Trainee in Pharmacology. Present address: Illinois Institute of Technology Research Institute, 10 West 35th St., Chicago, IL 60616.

³ Recipient of Research Career Development Award K04 CA00982.

⁴ To whom requests for reprints should be addressed, at Division of Surgical Oncology, University of Illinois School of Medicine at Chicago, 840 South Wood St., Chicago, IL 60612.

Received 2/25/87. Revised 6/ 8/87. Revised 12/21/87. Accepted 3/ 7/88.