Stability and capacity of dimethylnitrosamine-induced 06-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-methyiguanine 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 O⁸-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. Research.