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

Abstract

Abstract Male Sprague-Dawley (Charles River CD) rats received a single carcinogenic dose (12 mg/kg) of the α-acetoxy derivative of dimethylnitrosamine, N -[ 14 C]methyl- N -acetoxymethylnitrosamine, and were allowed to survive for 12 hr. Following i.v. injection, highest concentrations of 7-methylguanine and O 6 -methylguanine were present in DNA of the lung, the principal target organ in the carcinogenesis by N -methyl- N -acetoxymethylnitrosamine at this dosage by this route of application. Injection i.p. of a similar dose of N -[ 14 C]methyl- N -acetoxymethylnitrosamine led to preferential DNA alkylation in organs bordering the abdominal cavity, with highest levels of methylated purines in ileum and colon, the principal sites of tumorigenesis for this route of administration. Esterases potentially responsible for the bioactivation of N -methyl- N -acetoxymethylnitrosamine in vivo were found in all organs investigated, with the highest levels of activity being present in rat kidney and liver. Incubation of N -[ 14 C]methyl- N -acetoxymethylnitrosamine with DNA and esterases from rat kidney in vitro resulted in a pattern of methylated purines similar to that produced by N -methyl- N -nitrosourea and related methylating carcinogens, indicating that these agents, including dimethylnitrosamine, exert their biological effects through a common alkylating intermediate. Pretreatment of rat liver extracts with the esterase inhibitor diisopropyl fluorophosphate (10 −4 m) reduced both the decomposition of N -methyl- N -acetoxymethylnitrosamine and DNA alkylation in vitro by more than 90%.