Methylation of liver DNA guanine in hydrazine hepatotoxicity: dose-response and kinetic characteristics of 7-methylguanine and O6-methylguanine formation and persistence in rats.
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 two different analytical techniques. Methylation levels changed little with dose except for the highest dose (ca. LD50) at which the levels doubled. In a time-response study, rats were given 90 mg hydrazine/kg body wt. and killed 0.25 to 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 approximately 50% in 47 h; the half-life of O6-methylguanine in liver DNA was approximately 13 hr. Three or four, but not one or two, 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.
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism*; D006834:Hydrazines / Q000633:toxicity*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051381:Rats
D006834:Hydrazines; C029424:hydrazine; D006147:Guanine; C008450:7-methylguanine; D004247:DNA; C008449:O-(6)-methylguanine