Differential repair of O4-alkylthymidine following exposure to methylating and ethylating hepatocarcinogens

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Abstract
Recent experiments have demonstrated that O 6 -alkylguanine is rapidly removed from hepatocyte DNA following continuous exposure to 1,2-dimethylhydrazine or diethylnitrosamine. In contrast, O 4 ethyldeoxythymidine accumulates to concentrations more than 50 times greater than O 6 ethyldeoxyguanosine. Studies on the formation and persistence of O 4 methyldeoxythymidine in vivo have not been reported. This study reports the development of sensitive radiommune assays to O 4 ethyldeoxythymidine and O 4 ethyldeoxythymidine midine. Utilizing this method, the accumulation and removal of O 4 ethyldeoxythymidine and O 4 ethyldeoxythymidine in liver DNA from rats exposed to 1,2-dimethylhydrazine or diethylnitrosamine were measured. The results demonstrated that O 4 methyldeoxythymidine was formed at an O 6 methylguamne/O 4 methyldoxythymidine ratio of ˜100/1 and was repaired with a half-time of ˜20h. In contrast, O 4 ethyldeoxythymidine removal was 13 times slower with a t½ of -11 days after both pulse dose and cessation of continuous DEN administration. Combined with previously reported data, results presented here suggest that (i) despite a lower rate of formation, 0 becomes nearly equal in importance to 0 as a promutagenic adduct in hepatocytes from continuously exposed rats and (ii) differential repair of 0 adducts provides a mechanism that may explain in part the superior ability of ethylating versus methylating agents to induce hepato cellular carcinomas in the rat.
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