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Enhancement of Hydroxylation and Deglycosylation of 2'-Deoxyguanosine by Carcinogenic Nickel Compounds¹

Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, FCRF, Frederick, Maryland [K. S. K.]; and Laboratory of Chemical and Physical Carcinogenesis, BRI—Basic Research Program, NCI-FCRF, Frederick, Maryland [L. H.]

The effects of nickel subsulfide (Ni₃S₂) and nickel chloride [Ni(II)] on hydroxylation and deglycosylation of pure 2'-deoxyguanosine (dG) and on hydroxylation of guanine (Gu) residues in calf thymus DNA in the absence or presence of hydrogen peroxide (H₂O₂) and/or ascorbate (Ascb) were studied with the use of high-performance liquid chromatography. Incubation of 0.75 mM dG with 5 mg Ni₃S₂/ml (particle size <5 µm) at 37°C in aerated 50 mM Tris/HCl buffer, pH 7.4, resulted in slow hydroxylation of dG to 8-hydroxy-2'-deoxyguanosine (8-OH-dG). This effect was greatly enhanced by 20 mM H₂O₂. Ni(II) alone at concentrations up to 10 mM was inactive but produced 8-OH-dG in the presence of 20 mM H₂O₂; the latter caused no dG hydroxylation by itself. Both Ni₃S₂ and Ni(II) increased the formation of 8-OH-dG from dG exposed to H₂O₂ + Ascb. At pH 7.4 and constant concentrations of H₂O₂ and Ascb (20 and 8 mM, respectively), Ni(II) over the concentration range 1–10 mM raised the hydroxylation yield by up to five times that without Ni(II). Also, addition of 7.5 mM Ni(II) more than doubled the hydroxylation yield of Gu residues by the 20 mM H₂O₂ + 8 mM Ascb mixture (pH 7.4) in denatured DNA and doubled it in native DNA. Ni₃S₂ and Ni(II) alone had no effect on deglycosylation of dG and did not significantly influence the slow rate of Gu production from dG reacting with H₂O₂ or Ascb at pH 7.4. However, Ni(II), unlike Ni₃S₂, increased the extent of dG deglycosylation when added to the dG + H₂O₂ + Ascb system; 10 mM Ni(II) increased deglycosylation by a factor of 2.5 in 24 h. Thus, nickel carcinogens were shown for the first time to cause and/or enhance both hydroxylation and deglycosylation reactions of dG which may contribute to the observed genotoxic and carcinogenic effects of this metal.

¹ Research sponsored by the National Cancer Institute, Department of Health and Human Services, under contract No. N01-CO-74101 with Bionetics Research, Inc.

² To whom requests for reprints should be addressed, at Building 538, Room 205, NCI-FCRF, Frederick, MD 21701-1013.

Received 3/27/89. Revised 6/26/89. Accepted 8/ 4/89.

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