ELEVATED 8-HYDROXY-2'-DEOXYGUANOSINE LEVELS IN LUNG DNA OF A J MICE AND F344 RATS TREATED WITH 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AND INHIBITION BY DIETARY 1,4-PHENYLENEBIS(METHYLENE)SELENOCYANATE/

1,4-Phenylenebis(methylene)selenocyanate (p-XSC) is an effective chemo preventive agent against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanon e (NNK)-induced lung adenoma in female A/J mice. While p-XSC can effec tively inhibit NNK-induced DNA methylation in female A/J mice and in m ale F344 rats, its effect on NNK-induced oxidative DNA damage had not been determined. Thus, the effect of p-XSC on the levels of 8-hydroxy- 2'-deoxyguanosine (8-OH-dG) in lung DNA from A/J mice and F344 rats tr eated with NNK was examined. Mice were given NNK by gavage (0.5 mg/mou se in 0.2 ml corn oil, three times per week for 3 weeks) or by a singl e i.p. injection (2 mg/mouse in 0.1 ml saline) while maintained on a c ontrol diet (AIN-76A) or control diet containing p-XSC at 10 or 15 p.p .m. (as Se) starting 1 week before NNK administration and continuing u ntil termination. Mice were killed 2 h after the last NNK gavage in th e multiple administration protocol or 2 h after the single i.p. inject ion. Treatment with NNK by gavage significantly elevated the levels of 8-OH-dG in lung DNA of A/J mice from 0.7 +/- 0.1 to 1.6 +/- 0.2 adduc ts/10(5) 2'-deoxyguanosine (dG) (P < 0.001), while dietary p-XSC (at 1 0 p.p.m, Se) prevented significant elevation of the levels of this les ion caused by NNK, keeping them at 0.9 +/- 0.1 adducts/10(5) dG (P < 0 .003), Injection of NNK in saline also significantly increased the lev els of 8-OH-dG in lung DNA of A/J mice from 1.2 +/- 0.6 to 3.6 +/- 0.8 /10(5) dG adducts (P < 0.01), while dietary p-XSC (at 15 p.p.m. Se) ke pt these levels at 1.9 +/- 0.5 adducts/10(5) dG (P < 0.03). Rats were given a single i.p. injection of NNK (100 mg/kg body wt) in saline whi le being maintained on control diet (AIN-76A) or control diet containi ng p-XSC at 10 or 15 p.p.m. (as Se) starting 1 week before NNK adminis tration and continuing until termination. The rats were killed 2 h aft er injection. Treatment with NNK using this protocol significantly ele vated the levels of 8-OH-dG in lung DNA of F344 rats from 2.6 +/- 0.5 to 3.5 +/- 0.5 adducts/10(5) dG (P < 0.03), while dietary p-XSC (at 15 p.p.m. Se) kept the levels of this lesion at 2.2 +/- 0.6 adducts/10(5 ) dG (P < 0.01). Our findings suggest that the chemopreventive efficac y of p-XSC against NNK-induced lung tumorigenesis in A/J mice and F344 rats may be due in part to inhibition of oxidative DNA damage.