Methylation of liver DNA guanine in hydrazine hepatotoxicity: dose-response and kinetic characteristics of O6-methylguanine and formation and persistence in rats

Abstract

Fischer 344 or Sprague Dawley rats were fasted overnight and given orally 30-90 mg hydrazine/kg body wt. The presence of 7-methylguanine and O6-methylguanine in liver DNA was demonstrated 5 and 24 h after hydrazine administration using 2 different analytical techniques. Methylation levels changed little with dose except for the highest dose (about LD50) at which the levels doubled. In a time-response study rats were given 90 mg hydrazine/kg body wt and killed 0.25-96 h later. Both 7-methylguanine and O6-methylguanine were detected quantitatively in liver DNA from rats as early as 15 min after hydrazine administration. After maximum levels of methylguanines had formed, 7-methylguanine was removed from DNA at a rate of .apprx. 50% in 47 h; the half-life of O6-methylguanine in liver DNA was .apprx. 13 h. Three or 4 but not 1 or 2 daily administrations of 3 mg hydrazine/kg body wt also produced detectable levels of 7-methylguanine in rat liver DNA. Neither 7-methylguanine or O6-methylguanine was detected in comparable amounts of liver DNA from control animals. The study confirms the observation that hydrazine administration results in the formation of methylated guanines in liver DNA.