EPR spectroscopic investigation of the lability of oxygen in activated bleomycin: implications for the mechanism of bleomycin-mediated DNA degradation.
Bleomycin (BLM), an antitumor antibiotic, is capable of degrading DNA through the formation of activated BLM, an activated iron-oxygen complex of the drug with a unique EPR spectrum. A recent study [Rabow, L. E., McGall, G. H., Stubbe, J., & Kozarich, J. W. (1990) J. Am. Chem. Soc. 112, 3203-3208] has cast doubt onto the "hydroxyl-radical-rebound" mechanism, commonly accepted for cytochrome P-450 [McMurray, T.J., & Groves, J.T. (1985) in Cytochrome P-450: Structure, Mechanism, and Biochemistry (Ortiz de Montellano, P., Ed.) pp 1-28, Plenum, New York] and proposed for the anaerobic nucleic base release reaction of BLM, by demonstrating that the source of oxygen in the products of this reaction is solvent molecules and not molecular oxygen. A central issue in this debate is whether the oxygen of activated BLM is available for exchange with that of solvent. The lability of oxygen in activated BLM has been investigated through the use of EPR spectroscopy to measure the exchange of 17O (I = 5/2) between activated BLM and solvent. Evidence for the lack of oxygen exchange between activated BLM and solvent is presented, and the implications of this result for the mechanism of BLM-mediated DNA degradation are discussed.
Sam
J W
JW
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461.
Peisach
J
J
D001761:Bleomycin / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; D010100:Oxygen
D005609:Free Radicals; D006878:Hydroxides; D001761:Bleomycin; D017665:Hydroxyl Radical; D004247:DNA; D010100:Oxygen