Differential repair of O4-alkylthymidine following exposure to methylating and ethylating hepatocarcinogens.
Recent experiments have demonstrated that O6-alkylguanine is rapidly removed from hepatocyte DNA following continuous exposure to 1,2-dimethylhydrazine or diethylnitrosamine. In contrast, O4-ethyldeoxythymidine accumulates to concentrations more than 50 times greater than O6-ethyldexyguanosine. Studies on the formation and persistence of O4-methyldeoxythymidine in vivo have not been reported. This study reports the development of sensitive radioimmune assays to O4-methyldeoxythymidine and O4-ethyldeoxythymidine. Utilizing this method, the accumulation and removal of O4-methyldeoxythymidine and O4-ethyldeoxythymidine in liver DNA from rats exposed to 1,2-dimethylhydrazine or diethylnitrosamine were measured. The results demonstrated that O4-methyldeoxythymidine was formed at an O6-methylguanine/O4-methyldeoxythymidine ratio of approximately 100/1 and was repaired with a half-time of approximately 20 h. In contrast, O4-ethyldeoxythymidine removal was 13 times slower with a t 1/2 of approximately 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, O4-methyldeoxythymidine becomes nearly equal in importance to O6-methylguanine as a promutagenic adduct in hepatocytes from continuously exposed rats and (ii) differential repair of O4-alkylthymidine adducts provides a mechanism that may explain in part the superior ability of ethylating versus methylating agents to induce hepatocellular carcinomas in the rat.
D019813:1,2-Dimethylhydrazine; D000818:Animals; D002273:Carcinogens; D004273:DNA, Neoplasm / Q000378:metabolism; D004052:Diethylnitrosamine / Q000494:pharmacology*; D004127:Dimethylhydrazines / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D009602:Nitrosamines / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D011916:Rats, Inbred F344; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism
D002273:Carcinogens; D004273:DNA, Neoplasm; D004127:Dimethylhydrazines; D008763:Methylhydrazines; D009602:Nitrosamines; D004052:Diethylnitrosamine; C008505:O-methylthymidine; C030119:O(4)-ethylthymidine; D019813:1,2-Dimethylhydrazine; D013936:Thymidine