title: 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.
abstract: 8-Oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) is an enzyme which prevents incorporation into DNA of promutagenic 8-oxo-2'-deoxyguanosine (8-oxo-dG) from a deoxynucleotide pool damaged by endogenous oxidants. Its inhibition may thus be carcinogenic. We previously found that Cd(II) inhibited 8-oxo-dGTPase in both cell free systems and cultured cells. To verify this finding in a relevant animal model, we investigated the effects of Cd(II) on cellular 8-oxo-dGTPase activity and nuclear DNA 8-oxo-dG levels in the rat testis, a target organ for Cd(II) carcinogenesis. Ni(II), which does not induce testicular tumors in rats and is a weaker in vitro inhibitor of 8-oxo-dGTPase than Cd(II), was investigated as a comparison. Male F344/NCr rats were given a single s.c. dose of 20 micromol Cd(II) acetate, 90 micromol Ni(II) acetate or 180 micromol sodium acetate (controls) per kg body wt and killed 2, 8, 24 or 48 h later (three rats/time point). Cd(II) caused a gradual decrease in testicular 8-oxo-dGTPase activity with time. It became significant only after 8 h post-injection (P < 0.05) and resulted in a final 50% loss of the enzyme activity at 48 h (P < 0. 01). Although the results for Ni(II) at 8 h and later were apparently lower than the controls, the decrease did not reach statistical significance. Treatment of rats with Cd(II) led to an early and progressive increase (from 130% at 2 h to 200% at 48 h versus the controls) of the 8-oxo-dG level in testicular DNA (P < 0. 05 or better). Ni(II) acetate also tended to raise the testicular 8-oxo-dG level, but the increase was transient, with an apparent maximum at 8 h, and did not approach statistical significance (P < 0. 2). Thus, Cd(II), unlike Ni(II), is able to inhibit 8-oxo-dGTPase activity and to raise 8-oxo-dG levels in rat testicular DNA. However, the time course of both effects indicates that 8-oxo-dGTPase inhibition is most likely not the sole cause of the increase in 8-oxo-dG.
authors.affiliation: Laboratory of Comparative Carcinogenesis, National Cancer Institute and Intramural Research Support Program, SAIC Frederick, FCRDC, Frederick, MD 21702, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bialkowski
authors.forename: A
authors.initials: A
authors.lastname: Bialkowska
authors.forename: K S
authors.initials: KS
authors.lastname: Kasprzak
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D002104:Cadmium / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000085:Acetates; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D002104:Cadmium; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C028031:cadmium acetate; C119536:nickel acetate; D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine