Hydroxylation and deglycosylation of 2'-deoxyguanosine in the presence of magnesium and nickel.
Nickel (Ni), a carcinogenic and genotoxic metal, has been shown to enhance deglycosylation and hydroxylation of 2'-deoxyguanosine (dG) that has been caused by ascorbic acid and H2O2. There is evidence that Mg is a competitive antagonist of the toxicological effects of Ni. A factorial design was used to examine the interactive influence of Mg and Ni on the deglycosylation and hydroxylation of dG under a range of pH conditions in which ascorbate (Ascb) and H2O2 were added. Formation of guanine (Gu) (deglycosylation) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) (hydroxylation) appeared in large amounts in samples in which both H2O2 and Ascb were present. The largest amounts of Gu appeared where both Ni or magnesium (Mg) were present. When Mg alone was present, the amounts of Gu was intermediate between these two. Slightly less 8-OH-dG was formed where only Mg was present. The reaction mixtures were more sensitive to the pH than to the respective presence or absence of metals. At slightly acid or neutral pH (6.2-7.0) large amounts of both Gu and 8-OH-dG were formed. Gu formation decreased dramatically between pH 7.0 and 7.2. There was no 8-OH-dG formed at pH 7.8 and only small amounts at pH 7.6. The formation of 8-OH-dG was generally less where Mg was present. When Ni was absent, 8-OH-dG formation was greater in the pH 6.8 mixtures. The formation of Gu and 8-OH-dG from 2'-deoxyguanosine are directly a function of pH. Slight changes in pH greatly effected the formation of these biomarkers of oxidatively damaged DNA. Additional research is needed to determine if this is a cause or effect, i.e. does pH enhance toxicity conditions, thus permitting formation of 8-OH-dG, or does pH permit the reaction to proceed.
Littlefield
N A
NA
Department of Health and Human Services, Food and Drug Administration, Jefferson, AR 72079.
Fullerton
F R
FR
Poirier
L A
LA
D001205:Ascorbic Acid / Q000633:toxicity; D001711:Biotransformation; D003849:Deoxyguanosine / Q000378:metabolism* / Q000493:pharmacokinetics; D006031:Glycosylation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D006900:Hydroxylation / Q000187:drug effects; D008274:Magnesium / Q000633:toxicity*; D009532:Nickel / Q000633:toxicity*
D009532:Nickel; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine; D008274:Magnesium; D001205:Ascorbic Acid