Montesano R
J Supramol Struct Cell Biochem. 1981;17(3):259-73. doi: 10.1002/jsscb.380170307.
A peculiarity of nitrosamines is the high degree of cell and organ specificity in inducing tumors. There is substantial evidence that the initiation of the carcinogenesis process by carcinogens of this group is linked to the metabolic competence of the target tissue or cell to convert these carcinogens into mutagenic metabolites and to the binding of those metabolites to cellular DNA. Alkylation occurs in the DNA at the N-1, N-3, and N-7 positions of adenine; the N-3, N-7, and O6 of guanine; the N-3, and O2 of cytosine; and the N-3, O4, and O2 of thymine; and the phosphate groups. The initial proportion of each DNA adduct depends upon the alkylating agent used. The various DNA adducts are lost to a variable extent from DNA in vivo by spontaneous release of bases and/or by specific DNA repair processes. Studies conducted in vitro and vivo indicate that alkylation at the oxygen atoms of DNA bases is more critical than alkylation at other positions in the mutagenesis and carcinogenesis induced by N-nitroso compounds. In particular, tissues in which tumors occur more frequently after a pulse dose of nitrosamine are those in which O6-alkylguanine persists longest in DNA, presumably resulting in an increased probability that a miscoding event (mutation) will take place during DNA synthesis. The more rapid removal of O6-methylguanine from the DNA of liver (as compared with extrahepatic tissues) of rats has been associated with the absence of tumor production in this organ by a single dose of dimethylnitrosamine; however, a significant incidence of liver tumors is observed if the same dose is given 24 hr after partial hepatectomy, and tumors are induced by such a dose of dimethylnitrosamine in the liver of hamsters, which has a low capacity to remove O6-methylguanine from its DNA. These data also indicate that the rate of disappearance of 7-methylguanine from the liver or extrahepatic tissues is independent of the dose of dimethylnitrosamine; whereas O6-methylguanine is lost from DNA more rapidly after a low dose of this nitrosamine. It has been shown that in liver the removal of O6-methylguanine but not other DNA adducts, from DNA can be affected by pretreating the animals with N-nitroso compounds. The modulation of DNA repair processes observed after a single dose and after chronic treatment with nitrosamines is discussed in relation to the tissue-specific carcinogenic effect of this group of carcinogens.
亚硝胺的一个特点是在诱导肿瘤方面具有高度的细胞和器官特异性。有大量证据表明，这类致癌物引发致癌过程与靶组织或细胞将这些致癌物转化为诱变代谢物的代谢能力以及这些代谢物与细胞DNA的结合有关。烷基化发生在DNA中腺嘌呤的N-1、N-3和N-7位；鸟嘌呤的N-3、N-7和O6位；胞嘧啶的N-3和O2位；胸腺嘧啶的N-3、O4和O2位；以及磷酸基团。每种DNA加合物的初始比例取决于所使用的烷基化剂。在体内，各种DNA加合物会因碱基的自发释放和/或特定的DNA修复过程而从DNA中不同程度地丢失。体外和体内研究表明，在由N-亚硝基化合物诱导的诱变和致癌过程中，DNA碱基氧原子处的烷基化比其他位置的烷基化更为关键。特别是，在给予脉冲剂量的亚硝胺后更易发生肿瘤的组织，是那些O6-烷基鸟嘌呤在DNA中持续时间最长的组织，这大概会增加在DNA合成过程中发生错配事件（突变）的可能性。大鼠肝脏（与肝外组织相比）DNA中O6-甲基鸟嘌呤的去除速度更快，这与单剂量二甲基亚硝胺不会在该器官产生肿瘤有关；然而，如果在部分肝切除术后24小时给予相同剂量，则会观察到肝脏肿瘤的显著发生率，并且这样剂量的二甲基亚硝胺会在仓鼠肝脏中诱导肿瘤，仓鼠肝脏从其DNA中去除O6-甲基鸟嘌呤的能力较低。这些数据还表明，肝脏或肝外组织中7-甲基鸟嘌呤的消失速率与二甲基亚硝胺的剂量无关；而在低剂量的这种亚硝胺作用后，O6-甲基鸟嘌呤从DNA中丢失得更快。已经表明，在肝脏中，用N-亚硝基化合物预处理动物会影响DNA中O6-甲基鸟嘌呤的去除，但不会影响其他DNA加合物的去除。本文讨论了在给予单剂量和长期用亚硝胺处理后观察到的DNA修复过程的调节与这类致癌物的组织特异性致癌作用之间的关系。
