S. Hix et O. Augusto, DNA methylation by tert-butyl hydroperoxide-iron (II) - A role for the transition metal ion in the production of DNA base adducts, CHEM-BIO IN, 118(2), 1999, pp. 141-149
Metabolic degradation of both endogenous and exogenous peroxides is associa
ted with the etiology of several diseases including cancer. Tert-butyl hydr
operoxide (TBHP) has been widely employed as a model compound to study the
cytotoxicity and promoting effects of organic peroxides. Recently, we repor
ted that incubations of TBHP with iron (II) and calf thymus DNA led to gene
ration of high yields of methyl radicals and to DNA methylation. Interestin
gly, DNA was methylated to products expected from both free radical and ion
ic mechanisms such as 8-methylguanine (C-8-MeGua) and 7-methylguanine (N-7-
MeGua), respectively. To elucidate the mechanisms by which methyl radicals
can produce different types of DNA adducts, we examined the effects of tran
sition metal ions (iron (II), iron (III) and copper (I)) and metal ion chel
ators (ethylenediamine-N,N, N ",N "-tetraacetate (EDTA) and desferal) on th
e nature and the yields of the DNA adducts produced during TBHP decompositi
on. The results led us to propose that a direct methyl radical attack on DN
A guanine residues produces C-8-MeGua whereas N-7-MeGua and 3-methyladenine
(N-3-MeAde) are likely to be produced by attack of nucleophilic DNA center
s on methyl radical generated in situ by the assistance of transition metal
ions bound to DNA. (C) 1999 Elsevier Science Ireland Ltd. All rights reser
ved.