Inhibition of antimutagenic enzymes, 8-oxo-dGTPases, by carcinogenic metals. Recent developments

Nickel, cadmium, cobalt, and copper are carcinogenic to humans and/or anima ls, but the underlying mechanisms are poorly understood. Our studies have b een focused on one such mechanism involving mediation by the metals of prom utagenic oxidative damage to DNA bases. The damage may be inflicted directl y in DNA or in the deoxynucleotide pool, from which the damaged bases are i ncorporated into DNA. Such incorporation is prevented in cells by 8-oxo-2'- deoxyguanosine 5'-triphosphate pyrophosphatases (8-oxo-dGTPases). Thus, inh ibition of these enzymes should enhance carcinogenesis. We have studied eff ects of Cd(II), Cu(II), Co(II), and Ni(II) on the activity of isolated bact erial and human 8oxo-dGTPases. Cd(II) and Cu(II) were strongly inhibitory, while Ni(II) and Co(II) were much less suppressive. After developing an ass ay for 8-oxo-dGTPase activity, we confirmed the inhibition by Cd(II) in cul tured cells and in the rat testis, the target organ for cadmium carcinogene sis. 8Oxo-dGTPase inhibition was accompanied by an increase in the g-oxo-dG level in testicular DNA. (C) 2000 Elsevier Science Inc. All rights reserve d.