Correlation of DNA methylation by methyl(acetoxymethyl)nitrosamine with organ-specific carcinogenicity in rats.

Male Sprague-Dawley (Charles River CD) rats received a single carcinogenic dose (12 mg/kg) of the a-acetoxy deniva tive of dimethylnitrosammne,N-[14C]methyl-N-acetoxymethylni trosamine, and were allowed to survive for 12 hr. Following iv. injection, highest Concentrations of 7-methylguanine and Q6@ methylguanine were present in DNA of the lung, the principal target organ in the carcinogenesis by N-methyl-N-acetoxy methylnitmosammne at this dosage by this route of application. Injection i.p. of a similar dose of N-['4C]methyl-N-acetoxy methylnitrosamine led to preferential DNA alkylation in organs bordering the abdominal cavity, with highest levels of methyl ated purines in ileum and colon, the principal sites of tumori genesis for this route of administration. Estemasespotentially responsible for the bioactivation of N-methyl-N-acetoxymethyl nitmosaminein vivo were found in all organs investigated, with the highest levels of activity being present in matkidney and liver. Incubation of N-[14C]methyl-N-acetoxymethylnitrosamine with DNA and estemasesfrom matkidney in vitro resulted in a pattern of methylated puminessimilar to that produced by Nmethyl-N-nitrosoumeaand related methylating carcinogens, in dicating that these agents, including dimethylnitrosamine, exert their biological effects through a common alkylating intemme diate. Pretreatment of rat liver extracts with the esterase inhib itomdiisopropyl fluomophosphate (1O@ M) reduced both the decomposition of N-methyl-N-acetoxymethylnitrosamine and DNA alkylation in vitro by more than 90%.