Exhaustion and recovery of repair excision of O⁶-methylguanine from rat liver DNA

Abstract

EVIDENCE continues to accumulate that the O⁶ position of guanine in DNA is a critical reaction site for the initiation of malignant transformation by monofunctional alkylating agents. O⁶-alkylguanine has been shown to be promutagenic and the relative extent of its formation by different compounds approximately corresponds to their carcinogenic potency^1–3. In contrast to 7-alkylguanine, which is the major reaction product in nucleic acids, O⁶-alkylguanine can be enzymically excised from DNA^4–7 and the tissue-specific carcinogenic action of alkylating carcinogens seems to depend on the differential capacity of the various organs to actively remove this base from their DNA^8–11. The principal target organ in the carcinogenicity of N-methyl-N-nitrosourea (MNU) is the nervous system and it has been shown that O⁶-methylguanine (O⁶-meG) is removed much less rapidly from brain DNA than from that of any other rat tissue^9,11. The liver is not susceptible to the carcinogenicity of MNU (except after partial hepatectomy¹²) and this organ has been found to be most efficient in the repair excision of O⁶-meG (ref. 11). We have noted⁹, however, that the loss of O⁶-meG from liver DNA is influenced markedly by the dose of MNU administered; higher levels of O⁶-meG are less rapidly removed. We now present evidence that the excision repair system for O⁶-meG in rat liver can be overloaded with sublethal doses of MNU and related carcinogens, and requires several days to recover and restore its initial capacity.