Stability and capacity of dimethylnitrosamine-induced O6-methylguanine repair system in rat liver

Cancer Res. 1983 Dec;43(12 Pt 1):5808-14.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylation
  • Animals
  • DNA Repair / drug effects*
  • DNA Replication / drug effects
  • Dimethylnitrosamine / metabolism
  • Dimethylnitrosamine / toxicity*
  • Guanine / analogs & derivatives*
  • Guanine / metabolism
  • Kinetics
  • Liver / drug effects*
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Inbred Strains

Substances

  • Guanine
  • O-(6)-methylguanine
  • Dimethylnitrosamine