Dimethylnitrosamine inhibits enzymatic removal of O⁶-methylguanine from DNA

Abstract

THE induction of tumours by dimethylnitrosamine and N-methyl-N-nitrosourea is thought to be initiated by the methylation of cellular constituents^1–3. Recent results have suggested that a critical product produced by these carcinogens and their ethyl analogues might be O⁶-alkylguanine in DNA^2–5. Organs relatively resistant to the carcinogenic stimulus provided by these agents seem to have a greater ability to remove this alkylated purine from their DNA than more sensitive tissues^5–8. The activity of the system responsible for the removal of O⁶-methylguanine from DNA may, therefore, play an important part in determining whether tumours are produced. The ability to remove O⁶-methylguanine from DNA in rat kidney and liver showed a striking change in response to the dose of carcinogen administered. Large single doses of dimethylnitrosamine (20 mg per kg body weight or greater) which produce renal tumours in rats^1,2 led to almost complete cessation of the excision of this product from kidney DNA⁸. In the rat liver removal of O⁶-methylguanine still occurred after high doses of dimethylnitrosamine or N-methyl-N-nitrosourea but was much less efficient than after smaller doses^9–11. All of the studies summarised above were carried out by following the persistence of labelled O⁶-alkylguanine in DNA in vivo following administration of radioactive N-nitroso-compounds. This report describes a comparison of the abilities of extracts derived from liver and kidneys of control rats and rats pretreated with dimethylnitrosamine to catalyse the loss of O⁶-methylguanine from acid-precipitable DNA in vitro.