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.