Detection of free-radical damage during reductive metabolism of benzotriazine-di-N-oxides

Benzotriazine-di-N-oxides are hypoxic cytotoxins. Because the two electron reduction products, the mono-N-oxides, were not cytotoxic, the radical anions were the presumed cytotoxic agents. Inhibition of reductive activation may be because of cytotoxic drug radical scavenging by O/sub 2/ or direct sensitivity of activating enzymes to O/sub 2/. Aerobic and hypoxic reduction of drug and production of thiobarbituric acid reactive substances (TBARS) in cells, by liver microsomes, or by purified enzymes were compared. TBARS are indicative of oxygen radical damage. The experimental results of TBARS detection are given. The authors conclude that oxygen radical damage was, detected during both aerobic and hypoxic metabolism of the benzotriazines