Reductive metabolism of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) and the induction of unscheduled DNA synthesis in rat and human derived cell lines

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Abstract
The cellular and microsomal reductive metabolism of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233) was studied aerobically and anaerobically in rat (JB1, BL8, Walker) mouse (3T3) and human (HepG2) derived cell lines. In all cases rates or reduction to the mono-N-oxide (SR 4317) were greater under anaerobic than aerobic conditions when determined using HPLC with UV and fluorescence detection. Of the rat derived cells, a transformed liver epithelial line (JB1) showed the greatest cellular and microsomal rates of reduction while Walker 256 carcinoma cells showed the lowest. Microsomal reduction of SR 4233 was the highest in preparations from rat liver but carbon monoxide did not inhibit the reaction, suggesting cytochrome P450 was not involved. Purified cytochrome P450 reductase could carry out the reduction of SR4233. Rates of reduction of SR4233 in microsomal preparations from the cell lines and In rat liver nuclei correlated with activities of cytochrome P450 reductase. Activation of SR 4233 to cause cellular DNA damage was measured using unscheduled DNA synthesis as an index. Under anaerobic conditions, SR 4233 caused a dose-dependent increase in unscheduled DNA synthesis. Only a slight increase occurred following aerobic incubation. No increase was seen using the reduced metabolites SR 4317 or SR 4330. Of the cell lines studied, Walker cells showed the highest induction of unscheduled DNA synthesis. It was concludced that rates of reduction of SR 4233 did not necessarily reflect the potential DNA-damaging effects of this compound.

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