Mechanisms of nickel carcinogenesis. Interaction of Ni(II) with 2'-deoxynucleosides and 2'-deoxynucleotides.
Interactions of Ni(II) with the base moieties of 2'-deoxynucleosides and 2'-deoxynucleotides were studied by means of UV difference spectroscopy in order to elucidate the mechanisms of site-specific enhancement by Ni(II) of DNA base oxidation with active oxygen species, observed previously (Kasprzak et al., Cancer Res., 49 (1989) 5964; Carcinogenesis, 11 (1990) 647). The interactions were generally weak and could be quantitated only at pH 7.2-7.9. The resulting coordination binding of Ni(II) was stronger with the purine derivatives, especially these of guanine, than with pyrimidine derivatives. Also, Ni(II) interacted more strongly with the bases of 2'-deoxynucleotides than with the bases of 2'-deoxynucleosides. The apparent stability constants for the interactions calculated with the use of a non-linear regression method, equalled 102 +/- 14, 159 +/- 30 and 290 +/- 70 M-1 for Ni(II) coordinated by 5'dAMP, 5'dADP and 5'dATP, respectively, and 305 +/- 73, 191 +/- 54, and 270 +/- 28 M-1 for 5'dGMP, 5'dGDP and 5'dGTP, respectively. Stability constant for the dG Ni(II) interaction was 39 +/- 7 M-1. Interactions of Ni(II) with the bases of dA, dC, dT and the dC- and dT- mono-, di- and tri-phosphates were too weak for meaningful quantitation. The strongest relative Ni(II) interaction with dG may explain high sensitivity of the dG site at the DNA molecule to Ni(II)-mediated oxidation observed in vitro and in vivo. The present results contrast with Ni(II)-directed site specific cleavage of DNA with H2O2 that occurs preferentially at the pyrimidine bases (Kawanishi et al., Carcinogenesis, 10 (1989) 2231).
Laboratory of Comparative Carcinogenesis, National Cancer Institute-FCRDC, MD 21702-1201.
A K
AK
Datta
C W
CW
Riggs
M J
MJ
Fivash
K S
KS
Kasprzak
D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D004247:DNA / Q000187:drug effects; D003853:Deoxyribonucleosides / Q000378:metabolism*; D003854:Deoxyribonucleotides / Q000378:metabolism*; D004347:Drug Interactions; D009532:Nickel / Q000378:metabolism* / Q000633:toxicity; D013056:Spectrophotometry, Ultraviolet
D002273:Carcinogens; D003853:Deoxyribonucleosides; D003854:Deoxyribonucleotides; D009532:Nickel; D004247:DNA