Carcinogenesis, Vol 18, 1785-1791, Copyright © 1997 by Oxford University Press
DW Porter, H Yakushiji, Y Nakabeppu, M Sekiguchi, MJ Fivash Jr and KS Kasprzak
The toxicity of Ni(II), Co(II) and Cu(II) in animals, and that of Cd(II) in
cultured cells, has been associated with generation of the promutagenic
lesion 8-oxo-7,8-dihydroguanine (8-oxoguanine) in DNA, among other effects.
One possible source of this base may be 8-oxo-7,8-
dihydro-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP), a product of
oxidative damage to the nucleotide pool, from which it is incorporated into
DNA. To promote such incorporation, the metals would have to inhibit
specific cellular 8-oxo-dGTPases that eliminate 8-oxo-dGTP from the
nucleotide pool. The present study was designed to test such inhibition in
vitro on 8-oxo-dGTPases from two different species, the human MTH1 protein
and Escherichia coli MutT protein. In the presence of Mg(II), the natural
activator of 8-oxo-dGTPases, all four metals were found to inhibit both
enzymes. For MTH1, the IC50 values (+/- SE; n = 3-4) were 17 +/- 2 microM
for Cu(II), 30 +/- 8 microM for Cd(II), 376 +/- 71 microM for Co(II) and
801 +/- 97 microM for Ni(II). For MutT, they were 60 +/- 6 microM for
Cd(II), 102 +/- 8 microM for Cu(II), 1461 +/- 96 microM for Ni(II) and 8788
+/- 1003 microM for Co(II). Thus, Cu(II) and Cd(II) emerged as much
stronger inhibitors than Ni(II) and Co(II), and MTH1 appeared to be
generally more sensitive to metal inhibition than MutT. Interestingly, in
the absence of Mg(II), the activity of the enzymes could be restored by
Co(II) to 73% of that with Mg(II) alone for MutT, and 34% for MTH1, the
other metals being much less or non-effective. The difference in
sensitivity to metal inhibition between the two enzymes may reflect the
differences in the amino acid ligands, especially the cysteine ligand,
outside their evolutionarily conserved Mg(II)-binding active sites, which
might indicate predominantly non-competitive or uncompetitive mechanism of
the inhibition. The overall results suggest that inhibition of 8-oxo-
dGTPases may be involved in the mechanisms of induction of the 8-
oxoguanine lesion in DNA by the metal ions studied, especially the non-
redox-active Cd(II) cation.
ARTICLES
Sensitivity of Escherichia coli (MutT) and human (MTH1) 8-oxo-dGTPases to in vitro inhibition by the carcinogenic metals, nickel(II), copper(II), cobalt(II) and cadmium(II)
Laboratory of Comparative Carcinogenesis, National Cancer Institute- FCRDC, Frederick, MD 21702, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sakai, M. Furuichi, M. Takahashi, M. Mishima, S. Iwai, M. Shirakawa, and Y. Nakabeppu A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by Human MTH1 J. Biol. Chem., March 1, 2002; 277(10): 8579 - 8587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bialkowski, A. Bialkowska, and K. S. Kasprzak Cadmium(II), unlike nickel(II), inhibits 8-oxo-dGTPase activity and increases 8-oxo-dG level in DNA of the rat testis, a target organ for cadmium(II) carcinogenesis Carcinogenesis, August 1, 1999; 20(8): 1621 - 1624. [Abstract] [Full Text] [PDF]
|
|