DNA damaging reactions

Nitrenium ions, particularly the arylnitrenium ions, have been proposed as intermediates in deoxyribonucleic acid (DNA) damaging reactions that can ultimately convert a normal cell into a cancer cell. Carcinogenesis is a complex phenomenon. 

Under hypoxic conditions, cellular enzymes reduce the benzotriazine di-N-oxide [(reaction (68) P450 reductase Cahill and White 1990 and NADPH may be involved Walton et al. 1992 Wang et al. 1993]. Upon microsomal reduction of tirapazamine the radical formed in reaction (68) has been identified by EPR (Lloyd et al. 1991). Using the pulse radiolysis technique, it has been shown that this radical has a pKd of 6 (Laderoute et al. 1988), and it is the protonated form that undergoes the DNA damaging reaction (Wardman et al. 2003). The rate constants of the bimolecular decay of the radical [reaction (70)] has been found to be 2.7 x 107 dm3 mol-1 s 1. The reaction with its anion is somewhat faster (8.0 x 108 dm3 mol-1 s 1), while the deprotonated radicals do not react with one another at an appreciable rate. From another set of pulse radiolysis data, a first-order process has been extracted (k = 112 s 1) that has been attributed to the water elimination reaction (72), and the tirapazamine action on DNA [reaction (74)] has been considered to be due to the resulting radical (Anderson et al. 2003). 

The SWV peak at 1.05 V vs. SCE for Ru(bpy)i+ increased with time of the DNA damage reaction (Fig. 9). As in the case where enzyme-free films are incubated directly with DNA damage agents, ds-DNA in the film is damaged by styrene oxide. As a result of these reactions, guanines are released from the protection of the double helix, as are adducts of adenine.[45] These species are more easily oxidized than the original ds-DNA, and the catalytic oxidation current increases. 

Figure 28.2 DNA Replication, damage, and repair. Some errors (shown as a black dot) may occur in the replication processes. Additional defects (shown in yellow) including modified bases, crosslinks, and single- and double-strand breaks are introduced into DNA by subsequent DNA-damaging reactions. Many of the errors are detected and subsequently repaired,...

Solution Properties of Metallobleomycins Related to the DNA Damage Reaction... 

What has become clear recently is that the alteration of metal domain properties upon binding to DNA occurs only when the structure interacts with specific 5 -GpPyrimidine-3 sites. Such evidence along with NMR structural results described below strongly link the metal domain structure with site specification that precedes the DNA damage reactions. 

Fig. 3. Autoradiograph of [ P]ADP-ribosylated proteins in V-79 and variant cells. Cells were penneabilized and 1x10 cells incubated at 37°C for 15 min with 1 nM [ P] NAD (specific activity 7800 cpm/pmol) and 3(X) l nA DNase to induce maximal DNA damage. Reactions were stopped by addition of sample solution and boiled 2 min. Solubilized samples were electrophoresed on a SDS, 9% polyacrylamide slab gel with a 3% polyacrylamide stacking gel and the autoradiographed. Lanes A, B, and C represent V-79, variant ADPRT 54 and variant ADPRT 351, respectively. Autoradiographs were exposed for 24 hr. Molecular weights indicated on the left of autoradiograph were determined by Coomassie Brilliant Blue staining of standards included in the slab gel.

WEI H, CAO Q AND RAHN R o (1996) Inhibition of UV light- and Fenton reaction-induced oxidative DNA damage by the soybean isoflavone genistein. Carcinogenesis. 17 (1) 73-7. 

Reaction of chromium (VI). with hydrc en peroxide in the presence of glutathione reactive intermediates and resulting DNA damage. Chem. Res. Tox. 3, 595-603. 

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