DNA methylation by tert-butyl hydroperoxide-iron (II): a role for the transition metal ion in the production of DNA base adducts.
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.
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Departamento de Bioquímìca, Instituto de Química, Universidade de São Paulo, SP, Brazil.
Augusto
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D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D002417:Cattle; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D019175:DNA Methylation; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry; D007501:Iron / Q000737:chemistry*; D015394:Molecular Structure; D020122:tert-Butylhydroperoxide / Q000737:chemistry
D002614:Chelating Agents; D018736:DNA Adducts; D005609:Free Radicals; C066771:8-methylguanine; C025946:3-methyladenine; D006147:Guanine; C008450:7-methylguanine; D003300:Copper; D020122:tert-Butylhydroperoxide; C008449:O-(6)-methylguanine; D007501:Iron; D000225:Adenine