Hix S, Augusto O
Departamento de Bioquímìca, Instituto de Química, Universidade de São Paulo, SP, Brazil.
Chem Biol Interact. 1999 Apr 1;118(2):141-9. doi: 10.1016/s0009-2797(99)00079-4.
Metabolic degradation of both endogenous and exogenous peroxides is associated with the etiology of several diseases including cancer. Tert-butyl hydroperoxide (TBHP) has been widely employed as a model compound to study the cytotoxicity and promoting effects of organic peroxides. Recently, we reported that incubations of TBHP with iron (II) and calf thymus DNA led to generation of high yields of methyl radicals and to DNA methylation. Interestingly, DNA was methylated to products expected from both free radical and ionic mechanisms such as 8-methylguanine (C8-MeGua) and 7-methylguanine (N7-MeGua), respectively. To elucidate the mechanisms by which methyl radicals can produce different types of DNA adducts, we examined the effects of transition metal ions (iron (II), iron (III) and copper (I)) and metal ion chelators (ethylenediamine-N,N,N",N"-tetraacetate (EDTA) and desferal) on the nature and the yields of the DNA adducts produced during TBHP decomposition. The results led us to propose that a direct methyl radical attack on DNA guanine residues produces C8-MeGua whereas N7-MeGua and 3-methyladenine (N3-MeAde) are likely to be produced by attack of nucleophilic DNA centers on methyl radical generated in situ by the assistance of transition metal ions bound to DNA.
内源性和外源性过氧化物的代谢降解与包括癌症在内的多种疾病的病因有关。叔丁基过氧化氢（TBHP）已被广泛用作研究有机过氧化物细胞毒性和促进作用的模型化合物。最近，我们报道TBHP与铁（II）和小牛胸腺DNA孵育会产生高产率的甲基自由基并导致DNA甲基化。有趣的是，DNA被甲基化形成了分别由自由基和离子机制产生的产物，如8-甲基鸟嘌呤（C8-MeGua）和7-甲基鸟嘌呤（N7-MeGua）。为了阐明甲基自由基产生不同类型DNA加合物的机制，我们研究了过渡金属离子（铁（II）、铁（III）和铜（I））和金属离子螯合剂（乙二胺-N，N，N'，N'-四乙酸（EDTA）和去铁胺）对TBHP分解过程中产生的DNA加合物的性质和产率的影响。结果使我们提出，甲基自由基直接攻击DNA鸟嘌呤残基会产生C8-MeGua，而N7-MeGua和3-甲基腺嘌呤（N3-MeAde）可能是由与DNA结合的过渡金属离子协助原位产生的甲基自由基攻击亲核DNA中心而产生的。
