Inhibition of antimutagenic enzymes, 8-oxo-dGTPases, by carcinogenic metals. Recent developments.
Nickel, cadmium, cobalt, and copper are carcinogenic to humans and/or animals, but the underlying mechanisms are poorly understood. Our studies have been focused on one such mechanism involving mediation by the metals of promutagenic oxidative damage to DNA bases. The damage may be inflicted directly in DNA or in the deoxynucleotide pool, from which the damaged bases are incorporated into DNA. Such incorporation is prevented in cells by 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphatases (8-oxo-dGTPases). Thus, inhibition of these enzymes should enhance carcinogenesis. We have studied effects of Cd(II), Cu(II), Co(II), and Ni(II) on the activity of isolated bacterial and human 8-oxo-dGTPases. Cd(II) and Cu(II) were strongly inhibitory, while Ni(II) and Co(II) were much less suppressive. After developing an assay for 8-oxo-dGTPase activity, we confirmed the inhibition by Cd(II) in cultured cells and in the rat testis, the target organ for cadmium carcinogenesis. 8-Oxo-dGTPase inhibition was accompanied by an increase in the 8-oxo-dG level in testicular DNA.
Kasprzak
K S
KS
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201, USA. kasprkaz@mail.ncifcrf.gov
Bialkowski
K
K
D000818:Animals; D016466:CHO Cells; D002104:Cadmium / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D003035:Cobalt / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D006224:Cricetinae; D045643:DNA Repair Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008297:Male; D019216:Metals, Heavy / Q000494:pharmacology*; D009532:Nickel / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004791:Enzyme Inhibitors; D019216:Metals, Heavy; D002104:Cadmium; D003035:Cobalt; D003300:Copper; D009532:Nickel; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes