Stability and capacity of dimethylnitrosamine-induced O6-methylguanine repair system in rat liver.
Repeated administration of dimethylnitrosamine (DMN) (2 mg/kg for 3 weeks) to BD IV rats results in an increased capacity for the liver to repair O6-methylguanine in DNA, whereas other DNA adducts (7-methylguanine and 3-methyladenine) are not affected. In the experiments reported here, data on the rapidity of action of the enhanced system, its capacity after different challenging doses of [14C]DMN (0.2, 2.0, and 20 mg/kg), and the persistence after cessation of the DMN pretreatment are described. The results show that, after a dose of [14C]DMN (2.0 mg/kg), the increased activity acts very rapidly (10 min) repairing O6-methylguanine as soon as it is formed and that, by 2 hr, 65% of the O6-methylguanine generated in liver DNA has already been removed. Very little removal of O6-methylguanine occurs within this time in control rats not receiving any DMN pretreatment. The DMN-induced repair activity is of limited capacity, since its effect can be detected after DNA damage induced by 0.2 or 2.0 mg of [14C]DMN per kg, whereas this activity has little impact on the O6-methylguanine generated in liver DNA by 20 mg of [14C]DMN per kg. Upon cessation of the DMN pretreatment, the enhanced repair activity, as determined also by the in vitro activity of the O6-methyltransferase, decays slowly, but after 25 days, the repair activity is still higher than control values. No correlation was observed between increased [3H]thymidine incorporation in liver DNA and increased O6-methylguanine repair, indicating that liver cell proliferation is not necessarily coupled with an elevated methyltransferase level.
D000478:Alkylation; D000818:Animals; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000378:metabolism / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D006147:Guanine; C008449:O-(6)-methylguanine; D004128:Dimethylnitrosamine