Carcinogenesis, Vol. 20, No. 8, 1621-1624,
August 1999
© 1999 Oxford University Press
Carcinogenesis |
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
1 Laboratory of Comparative Carcinogenesis, National Cancer Institute and
2 Intramural Research Support Program, SAIC Frederick, FCRDC, Frederick, MD 21702, USA
3 On leave from Department of Clinical Biochemistry and
4 Department of Pathophysiology, University School of Medical Sciences, 85092 Bydgoszcz, Poland
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 µmol Cd(II) acetate, 90 µmol Ni(II) acetate or 180 µmol 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.
Abbreviations: CHO, Chinese hamster ovary; 8-oxo-dG, 8-oxo-2'-deoxyguanosine (8-hydroxy-2'-deoxyguanosine); 8-oxo-dGMP, 8-oxo-2'-deoxyguanosine 5'-monophosphate; 8-oxo-dGDP, 8-oxo-2'-deoxyguanosine 5'-diphosphate; 8-oxo-dGTP, 2'-deoxyguanosine 5'-triphosphate; 8-oxo-dGTPase, 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase.
5 To whom correspondence should be addressed Email: kasprkaz{at}mail.ncifcrf.gov
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