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 potency1–3. In contrast to 7-alkylguanine, which is the major reaction product in nucleic acids, O6-alkylguanine can be enzymically excised from DNA4–7 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 DNA8–11. 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 tissue9,11. 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.
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KLEIHUES, P., MARGISON, G. Exhaustion and recovery of repair excision of O6-methylguanine from rat liver DNA. Nature 259, 153–155 (1976). https://doi.org/10.1038/259153a0
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DOI: https://doi.org/10.1038/259153a0