DNA methylation by dimethylnitrosamine in the Mongolian gerbil (Meriones unguiculatus): indications of a deficient, noninducible hepatic repair system for O6-methylguanine.

Abstract

Abstract The formation of methylated purines in DNA of various gerbil tissues was determined following single i.p. injections (0.1 to 20 mg/kg) of dimethylnitrosamine (DMN). The extent of DNA methylation was highest in liver, followed by lung and kidney. In hepatic DNA, 7-methylguanine concentrations and amounts of DMN administered were directly proportional (305 µmol 7-methylguanine per mol guanine per mg DMN per kg body weight) over the entire dose range. At low doses, O 6 -methylguanine concentrations in gerbil liver amounted to much less than 11% of the respective 7-methylguanine values, indicating an enzymic repair during the 5-hr period following DMN administration. At doses higher than 0.5 mg per kg ( i.e. , above 17 µmol O 6 -methylguanine per mol guanine), no repair activity was detectable. Saturation of the hepatic O 6 -methylguanine repair at low substrate concentrations has also been observed in hamsters, whereas in mice and rats this system is operative at doses up to 5 mg DMN per kg. Pretreatment of gerbils with DMN (0.75 mg/kg/day) for 35 days did not increase the capacity of the liver to remove O 6 -[ 14 C]methylguanine from DNA after administration of [ 14 C]DMN. The capacity of cell-free extracts (80% ammonium sulfate precipitates of crude liver homogenates) of gerbils to remove O 6 -methylguanine from alkylated DNA in vitro was found to be about 25% of that of rats. There was no increase in the repair activity of gerbil liver extracts up to 96 hr after partial hepatectomy. These data indicate the presence in gerbil liver of a relatively deficient O 6 -methylguanine repair system which is not inducible by treatments shown to be effective in rat liver. In contrast, hepatic 7-methylguanine and 3-methyladenine DNA glycosylase activities were about 3 times higher in gerbils than in rats.