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 promutagenic^2,3. 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 neural^7,8 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-methylguanine^7,10. 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.