DNA damage by genotoxic hydroxyhalofuranones: an in silico approach to MX

MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone), a disinfection byproduct present in chlorinated drinking water, is one of the most potent mutagens known. Whereas its genotoxic effects are well documented, the mechanism by which MX exerts such an intense biological effect is still unclear. To gain further insight into both the general reactivity of hydroxyhalofuranones, and especially as regards their genotoxicity, here we report an in silico study of the aqueous reactivity of MX and two less powerful analogues (MXY, in general): (3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone -CMCF- and 3-chloro-4-(methyl)-5-hydroxy-2(5H)-furanone -MCF-). The following aspects were investigated: (i) the acid dissociation and isomerization equilibria of MXY, i.e. the species distribution among the possible isomers; (ii) the one-electron reduction potential of MXY; (iii) the guanosine and adenosine alkylation mechanism by MXY, which leads to covalent-DNA adducts; and (iv) the redox properties of the adducts. No significant differences were observed between MCF, CMCF, and MX, with a single exception: the unimolecular carbon-chlorine cleavage of some MX-nucleotide adducts may afford highly oxidative intermediates, which could be able to remove an electron from contiguous nucleotides directly, especially guanosine. This reaction would provide a pathway for the hypothesized ability of some hydroxyhalofuranones to oxidize DNA.