Differential repair of O4-alkylthymidine following exposure to methylating and ethylating hepatocarcinogens.
Differential repair of O4-alkylthymidine following exposure to methylating and ethylating hepatocarcinogens.
复制标题
暴露于甲基化和乙基化肝癌物质后 O4-烷基胸苷的差异修复。
作者：
F. Richardson;M. Dyroff;A. B. Joyce;J. Swenberg
最近的实验表明，在连续接触1，2-二甲基肼或二乙基亚硝胺后，O6-烷基鸟嘌呤可迅速从肝细胞DNA中移除。相比之下，O4-乙基脱氧胸苷的累积浓度是O6-乙基脱氧鸟苷的50倍以上。关于O4-甲基脱氧胸腺嘧啶核苷在体内的形成和持久性的研究尚未见报道。本研究建立了敏感的O4-甲基脱氧胸苷和O4-乙基脱氧胸苷放射免疫分析方法。用该方法测定了1，2-二甲基肼和二乙基亚硝胺对大鼠肝DNA中O_4-甲基脱氧胸苷和O_4-乙基脱氧胸苷的蓄积和清除。结果表明，O4-甲基脱氧胸腺嘧啶核苷在O6-甲基鸟嘌呤/O4-甲基脱氧胸腺嘧啶核苷的比值约为100：1时形成，半衰期约为20h，而脉冲给药和停止给药后，O4-乙基脱氧胸腺嘧啶核苷的去除速度减慢约13倍，t1/2约为11d。结合以前报道的数据，这里提供的结果表明：(I)尽管形成速度较低，但作为一种诱变加合物，O4-甲基脱氧胸苷在大鼠肝细胞中的重要性几乎与O6-甲基鸟嘌呤一样重要，(Ii)O4-烷基胸苷加合物的差异修复提供了一种机制，可能部分解释了乙基化比甲基化具有更强的诱发大鼠肝细胞癌的能力。
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.