Fuchs R P, Lang M C, Miller E C, Miller J A
Carcinogenesis. 1981;2(7):655-9. doi: 10.1093/carcin/2.7.655.
Earlier studies showed that N-acetyl-2-aminofluorene (AAF) is much more carcinogenic than N-acetyl-2-amino-7-iodofluorene (AAIF). Subsequently it was found that substitution of C-8 of guanine bases in DNA with AAF residues resulted in displacement of the guanine bases outside the DNA helix. This did not occur after similar substitution with AAIF residues. As one approach to assessing the possible importance of this gross conformational difference to the carcinogenicity of AAF, the carcinogenic activities of two electrophilic esters, N-myristoyloxy-AAF and its 7-iodo derivative, were compared by s.c. injection into male Fischer rats. On injection of a total of 64 mumol, each ester induced a high incidence of sarcomas, and the latent periods were similar. N-Myristoyloxy-AAIF was solvolyzed in aqueous media at about one-half the rate of N-myristoyloxy-AAF, and it was less than 10% as reactive with native DNA as N-myristoyloxy-AAF. N-Myristoyloxy-AAF and N-myristoyloxy-AAIF were each less reactive than the corresponding acetoxy derivatives. These data suggest that the low carcinogenicity of AAIF as compared to that of AAF may not be associated with the conformations of their adducts in the DNA. This difference in carcinogenicity may be related to differences in the rates of metabolic activation and inactivation of these two amides.
早期研究表明，N-乙酰-2-氨基芴（AAF）的致癌性比N-乙酰-2-氨基-7-碘芴（AAIF）强得多。随后发现，DNA中鸟嘌呤碱基的C-8位被AAF残基取代会导致鸟嘌呤碱基从DNA螺旋结构中移出。而用AAIF残基进行类似取代后则不会出现这种情况。作为评估这种总体构象差异对AAF致癌性可能重要性的一种方法，通过皮下注射到雄性Fischer大鼠体内，比较了两种亲电子酯N-肉豆蔻酰氧基-AAF及其7-碘衍生物的致癌活性。共注射64 μmol时，每种酯都诱发了高发性肉瘤，且潜伏期相似。N-肉豆蔻酰氧基-AAIF在水性介质中的溶剂解速率约为N-肉豆蔻酰氧基-AAF的一半，其与天然DNA的反应活性不到N-肉豆蔻酰氧基-AAF的10%。N-肉豆蔻酰氧基-AAF和N-肉豆蔻酰氧基-AAIF的反应活性均低于相应的乙酰氧基衍生物。这些数据表明，与AAF相比，AAIF的低致癌性可能与其在DNA中的加合物构象无关。这种致癌性差异可能与这两种酰胺的代谢活化和失活速率差异有关。
