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Formation and Loss of Alkylated Purines from DNA of Hamster Liver after Administration of Dimethylnitrosamine¹

Department of Physiology and Specialized Cancer Research Center, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania 17033 [R. S., A. E. P.]; International Agency for Research on Cancer, Unit of Chemical Carcinogeneis, 150 Cours Albert Thomas 69372 Lyon Cédex 2 France [R. M.]; and Paterson Laboratory, Christie Hospital and Holt Radium Institute, Manchester M20 BX, United Kingdom [G. P. M.]

The methylation of hamster liver DNA was studied as a function of dose of dimethylnitrosamine. 7-Methylguanine levels were proportional to a dose over the range of 10 µg/kg to 25 mg/kg when measured 5 to 24 hr after treatment. This product was lost from the DNA at a rate greater than expected from spontaneous depurination at neutral pH, suggesting that enzyme-catalyzed excision takes place. O⁶-Methylguanine levels were not proportional to doses over this range but were much lower than expected (based on 7-methylguanine levels) when measured 5 to 24 hr after doses of dimethylnitrosamine below 0.5 mg/kg. It is suggested that this result may be due to the presence of an enzyme capable of removing O⁶-methylguanine from DNA efficiently, provided the level of methylation was low. The presence of such an enzyme in hamster liver extracts was demonstrated by incubation with methylated DNA. The extracts brought about a significant decrease in the content of O⁶-methylguanine present in acid-precipitable DNA. However, when doses of dimethylnitrosamine above 0.5 mg/kg were used, removal of O⁶-methylguanine occurred much more slowly, and the capacity of hamster liver to carry out removal of O⁶-methylguanine from DNA in vivo was considerably lower than that of rat liver. The possible relevance of these findings to the relative susceptibility of these species to liver cancer induction by single doses of dimethylnitrosamine is discussed.

¹ This research was supported in part by Grants CA18137 and 1P30 CA18450 and by Contracts CP55630 and CP6-1063 from the National Cancer Institute, Department of Health, Education, and Welfare.

² To whom requests for reprints should be addressed.

Received 7/24/78. Accepted 9/28/78.

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