4-nitroquinoline-1-oxide (4-NQO) is a pro-oxidant carcinogen bioactivated by xenobiotic metabolism (XM). We investigated if antioxidants lycopene 0.45, 0.9, 1.8 μM, resveratrol 11, 43, 172 μM, and vitamin C 5.6 mM added or not with FeSO 0.06 mM, modulate the genotoxicity of 4-NQO 2 mM with the Drosophila wing spot test standard (ST) and high bioactivation (HB) crosses, with inducible and high levels of cytochromes P450, respectively. The genotoxicity of 4-NQO was higher when dissolved in an ethanol - acetone mixture. The antioxidants did not protect against 4-NQO in any of both crosses. In the ST cross, resveratrol 11 μM, vitamin C and FeSO resulted in genotoxicity; the three antioxidants and FeSO increased the damage of 4-NQO. In the HB cross, none of the antioxidants, neither FeSO , were genotoxic. Only resveratrol 172 μM + 4-NQO increased the genotoxic activity in both crosses. We concluded that the effects of the antioxidants, FeSO and the modulation of 4-NQO were the result of the difference of Cyp450s levels, between the ST and HB crosses. We propose that the basal levels of the XM's enzymes in the ST cross interacted with a putative pro-oxidant activity of the compounds added to the pro-oxidant effects of 4-NQO.