In vivo kinetics of O6-methylguanine and 7-methylguanine formation and persistence in DNA of rats treated with symmetrical dimethylhydrazine.

The rates of appearance and removal of 7-methylguanine and O6-methylguanine in DNA from rat liver, kidney, and colon were determined at various intervals up to 120 hr after i.p. administration of 10.2, 40.7, 81.5, or 163 mg 1,2-dimethylhydrazine (SDMH) per kg body weight (one-sixteenth, one-fourth, one-half, or one 50% lethal dose) using high-pressure liquid chromatography and fluorescence spectrophotometry. In most cases, increasing doses of SDMH slowed the rate of methylation of DNA, especially of the liver; colon DNA was methylated at a faster rate than was liver DNA, and kidney DNA was methylated at the slowest rate following SDMH administration. Removal of O6-methylguanine was slow (half-life, 37 to 50 hr) when this base was present in liver DNA at concentrations above 400 mumol/mol guanine; as the concentration fell below 300 mumol O6-methylguanine per mol guanine, the removal rate more than doubled (half-life, 16 to 19 hr). Some evidence was obtained to suggest that in the first 12 hr after maximum DNA methylation following SDMH administration, a rapid time-dependent removal of 7-methylguanine from liver and kidney but not colon DNA occurred. In these instances, then, the rates of formation and removal of aberrant methylated bases did not follow first-order kinetics.