Differentiated genotoxic response of carcinogenic and non-carcinogenic benzacridines and metabolites in rat hepatoma cells.

Two closely related hepatoma cell lines were examined for their genotoxic response to benacridines and their metabolites by the appearance of alkaline labile DNA sites: H5, a dedifferentiated line expressing cytochrome P-448-dependent mono-oxygenase(s); and HF1-4, a differentiated line expressing cytochrome P-450-dependent monooxygenase(s). The parent heterocycles had no effect on both cell lines. In contrast to the 3,4-dihydrodiol of benz[c]acridine the 3,4-dihydrodiol of benz[a]acridine induced no DNA strand breaks in both cell lines. All diol epoxides, however, induced DNA-damage in both cell lines, the syn derivatives in the same order of magnitude as the dihydrodiol of benz[c]acridine. The antidiol epoxides (epoxide group on the opposite side to the benzylic hydroxyl group) were the most potent to induce DNA-single strand breaks. The diol epoxide of benz[c]acridine was three times more efficient in HF1-4 than in H5, whereas for the diol epoxide of benz[a]acridine, the reverse was true. The results indicate that benz[c]acridine-3,4-diol is oxidized to metabolites which can induce DNA-damage. This is consistent with the hypothesis that the benz[a]acridine and derivatives are not easily metabolized to active mutagens but more likely are converted to inactive metabolites, possibly via N-oxidation. This is illustrated with 3,4-diol-1-2 anti-diol epoxide of benz[a]acridine which is inactivated in cell line HF1-4 due to the reactivity of the epoxide ring in the bay region. Since all diol epoxides show similar activity in both hepatoma cell lines, they are of great interest because of their ability to detect DNA-damaging agents and to analyse their metabolic activation and mechanism of action.