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.