Exhaustion and recovery of repair excision of O6-methylguanine from rat liver DNA
Exhaustion and recovery of repair excision of O6-methylguanine from rat liver DNA
复制标题
大鼠肝脏 DNA 修复切除 O6-甲基鸟嘌呤的耗尽和恢复
作者：
P. Kleihues;G. Margison
越来越多的证据表明，鸟嘌呤在DNA中的O6位置是单官能性烷基化试剂引发恶性转化的关键反应部位。已证明O6-烷基鸟氨酸具有致突变性，不同化合物形成O6-烷基鸟氨酸的相对程度大致相当于它们的致癌能力1-3。与核酸中的主要反应产物7-烷基鸟氨酸不同，O6-烷基鸟嘌呤可被酶从DNA4-7中去除，烷基化致癌物的组织特异性致癌作用似乎依赖于不同器官从其DNA8-11中主动去除该碱基的不同能力。N-甲基-N-亚硝胺(MNU)致癌的主要靶器官是神经系统，研究表明，O6-甲基鸟嘌呤(O6-Meg)从脑DNA中去除的速度比从任何其他大鼠组织中去除的速度要慢得多。肝脏对MNU的致癌性不敏感(除非部分肝切除12)修复切除O6-Meg最有效(参考文献)11)。然而，我们注意到，肝脏DNA中O6-Meg的丢失明显受MNU剂量的影响；较高水平的O6-Meg的清除速度较慢。我们现在提出的证据表明，大鼠肝脏中O6-Meg的切除修复系统可能因亚致死剂量的MNU和相关致癌物而超负荷，并需要数天时间才能恢复和恢复其最初的能力。
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.