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RV Lloyd, DR Duling, GV Rumyantseva, RP Mason and PK Bridson
Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
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.
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