Long-term persistence of O6-methylguanine in rat brain DNA.

Abstract

THE carcinogenic potency of alkylating agents correlates with the extent of their reaction at oxygen atoms in DNA bases1. O6-Alkylguanine is amongst those derivatives most likely to be involved in the initiation of malignant transformation since it leads to mispairing in vitro and thus can be considered promutagenic2,3. Repair excision of O6-alkylguanine from DNA has been demonstrated in bacteria4 and mammalian cells5, and seems to be initiated by a specific N-glucosidase6. In the intact animal, the persistence of O6-alkylguanine in DNA of different tissues varies considerably. In rats, the induction of neural7,8 and renal9 neoplasms correlates with a deficient excision capacity of the respective target tissues. O6-Alkylguanine produced by a single injection of the neuro-oncogenic agents N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea (MNU), is removed from brain DNA significantly more slowly than from that of liver and kidney, the half life in cerebral DNA being in the range of 9–11 d for both O6-ethyl- and O6-methylguanine7,10. These data are, however, based only on observations for up to 10 d. We report here that the decay curve for O6-methylguanine in brain DNA consists of different components and that this modified base may persist in cerebral DNA for a considerable fraction of the animal's life.