Cimetidine was administered by stomach tube to rats at 70 or 700 mg/kg, doses corresponding to 5 or 50 times, respectively, the typical daily dose of individuals on cimetidine treatment. In some cases, cimetidine (70 mg/kg) was administered in combination with a 2-fold molar excess of sodium nitrite. This treatment was carried out up to 6 times over a 3-day period, the pH of the rat stomach being maintained at 2.3 to 3.0 for about 1 hr after each treatment. The DNA of the stomach, liver, and intestines (large and small pooled together) was isolated 6 hr after cessation of treatment and analyzed for the presence of O6-methylguanine using a sensitive and specific radioimmunoassay. No evidence could be obtained for the presence of this methylated base in any of the DNA samples examined, the limit of detection being 3 µmol O6-methylguanine per mol guanine. We suggest that the observed lack of DNA methylation may be primarily due to the slow rate of nitrosation of cimetidine in combination with its rapid absorption into the blood stream.
This work was supported by Grant 80018 awarded by the Greek Agency for Research and Technology.