Craddock V M, Henderson A R
J Cancer Res Clin Oncol. 1986;111(3):229-36. doi: 10.1007/BF00389238.
Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation. Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.
已表明，在DNA修复过程中，几种O6-烷基鸟嘌呤加合物可通过将烷基转移至特定烷基腺嘌呤磷酸核糖基转移酶（AAP）中的半胱氨酸残基而从DNA上移除，同时形成S-烷基半胱氨酸。由于该反应是化学计量的且不可逆，细胞中的AAP含量可能会降低或耗尽。高剂量亚硝胺在体内造成的耗尽可用于检测鸟嘌呤O6位上可修复烷基化加合物的形成。此外，如果亚硝基化合物对特定器官的致癌效力与加合物在DNA中的持久性有关，那么效力将不取决于处理后达到的烷基化水平，而是取决于这是否足以耗尽相关器官的AAP含量从而减缓修复，即AAP的耗尽比DNA烷基化的初始程度更能准确反映效力。对靶器官和非靶器官的剂量反应研究表明，对于已知会使DNA甲基化的那些亚硝胺，AAP的耗尽与器官嗜性相关，即对于肝脏而言与N-亚硝基二甲胺（NDMA）相关，对于食管而言与N-甲基苄基亚硝胺（NMBzA）相关。对于N-亚硝基二乙胺（NDEA），结果支持了除O6-烷基鸟嘌呤之外可能还涉及其他加合物的观点。N-亚硝基-N-甲基苯胺（NMPhA）是一种食管特异性致癌物，它不会使食管中的AAP耗尽，反而会在肝脏中诱导AAP产生。这一结果进一步证明了NMPhA不会使DNA烷基化。
