Comparative Biochemistry and Metabolism. Part 1. Carcinogenesis

Oral administration of the inorganic hepatotoxin, hydrazine, to male Fischer 344 or Sprague Dawley rats results in the endogenous methylation of liver DNA at the 7- and O6-positions of guanine. At doses below the LD50 (45, 60 or 75 mg hydrazine/kg body weight), methylation levels varied little and averaged about 500micromol 7-methylguanine/mol guanine and 20 micromol O6- methylguanine/mol guanine. At 90 mg hydrazine/kg body weight (approximately the 7-day LD50) the methylation levels were 869 micromol 7-methylguanine and 58 micromol O6-methylguanine/mol guanine 24 hours after toxicant administration. A single dose of 3 mg hydrazine/kg body weight did not result in detectable levels of methylguanines in liver DNA; however, after three or four daily administrations of hydrazine at this dose, liver damage was evident, and liver DNA contained 50-100 micromol 7-methylguanine/mol guanine, about the limit of analytical detection. Following a single oral administration of 90 mg hydrazine/ kg body weight, liver DNA guanine rapidly became methylated. The time for half- maximum alkylation at 7-guanine was 30 minutes and at O6-guanine, 45 minutes. The rates of removal of these methylated bases were consistent with published values from experiments using methylating carcinogens and with values obtained in this laboratory with the model compound, 1,2-dimethylhydrazine.