Formation and Subsequent Repair of Alkylation Lesions in Tissues of Rodents Treated with Nitrosamines

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Abstract
There is evidence that the formation of O6-alkylguanine in DNA may be an important reaction in the induction of tumors by dimethylnitrosamine and related carcinogens. The removal of this product from DNA may protect against carcinogenesis. The removal process has been studied both in vivo after administration of labelled dimethylnitrosamine and in vitro by incubation of isolated enzyme preparations with alkylated DNA. It has been found that: 1. Activity removing O6-alkylguanine from DNA is present in a number of tissues, but is most active in liver. 2. High doses of dimethylnitrosamine (20 mg/kg) inhibit removal of O6-methylguanine from DNA in vivo completely in rat kidney and hamster liver and partially in rat liver. This loss of activity was also seen in extracts prepared from these tissues assayed in vitro. 3. Chronic exposure to low levels of dimethylnitrosamine led to an increase in the activity of the hepatic enzyme removing O6-methylguanine. 4. Hypophysectomy or thyroidectomy decreased the activity of the hepatic removal system for O6-methylguanine and treatment with growth hormone or thyroxin increased it. 5. Dimethyl- and diethylnitrosamine are rapidly absorbed from the upper part of the small intestine (but not from the stomach). The degree of alkylation observed in the liver was independent of whether the carcinogen was administered orally or by i.v. injection, but at doses of 0.1 mg/kg or less, the reaction with the kidney was much lower after oral administration. Therefore, at low oral exposures to the carcinogen, the liver, which has the greatest capacity to remove O6-methylguanine from its DNA receives a relatively greater proportion of the alkylation. These results are discussed in terms of the degree to which the DNA repair system removing O6-alkylguanine might contribute towards a threshold dose and that variations in this activity might be reflected in the magnitude of this threshold.