title: Microsomal reduction of 3-amino-1,2,4-benzotriazine 1,4-dioxide to a free radical.
abstract: 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.
authors.affiliation: Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
authors.forename: R V
authors.initials: RV
authors.lastname: Lloyd
authors.forename: D R
authors.initials: DR
authors.lastname: Duling
authors.forename: G V
authors.initials: GV
authors.lastname: Rumyantseva
authors.forename: R P
authors.initials: RP
authors.lastname: Mason
authors.forename: P K
authors.initials: PK
authors.lastname: Bridson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D003497:Cyclic N-Oxides; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D051381:Rats; D000077704:Tirapazamine; D014227:Triazines / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D005609:Free Radicals; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; C017245:5,5-dimethyl-1-pyrroline-1-oxide