TY - JOUR T1 - Microsomal reduction of 3-amino-1,2,4-benzotriazine 1,4-dioxide to a free radical. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 440 LP - 445 VL - 40 IS - 3 AU - R V Lloyd AU - D R Duling AU - G V Rumyantseva AU - R P Mason AU - P K Bridson Y1 - 1991/09/01 UR - http://molpharm.aspetjournals.org/content/40/3/440.abstract N2 - The drug SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide) is under pharmacological study as the lead compound in a new series of hypoxia-activated drugs, the benzotriazine N-oxides. However, the stable two- and four-electron-reduced metabolites of SR 4233, formed by the successive loss of the two oxygen atoms, are not pharmacologically active. In order to evaluate the possibility of an initial one-electron intermediate as the active species, we have used microsomal reduction and EPR spectroscopy to identify the first free radical reduction product. The unpaired electron is primarily centered on the 1-nitrogen, and the radical is best described as a nitroxide. Results with spin-trapping experiments show that reduction of SR 4233 to a free radical is followed by its air oxidation, resulting in the formation of the superoxide radical. Experiments with specific inhibitors suggest that the drug is being reduced by microsomal NADPH-cytochrome P-450 reductase. ER -