title: Characterization of the cycle of iron-mediated electron transfer from Adriamycin to molecular oxygen.
abstract: The anticancer drug adriamycin binds iron and these complexes cycle to reduce molecular oxygen (Zweier, J. L. (1984) J. Biol. Chem. 259, 6056-6058). Optical absorption, EPR, and Mössbauer spectroscopic data are correlated with polarographic O2 consumption and chemical Fe2+ extraction measurements in order to characterize each step in this cycle. Fe3+ binds to adriamycin at physiologic pH forming a complex with an optical absorbance maximum at 600 nm. EPR signals at g = 4.2 and g = 2.01, and a doublet Mössbauer spectrum with isomer shift delta = 0.57 mm/s and quadrupole splitting delta EQ = 0.74 mm/s are observed indicating that the Fe3+ bound to adriamycin is high spin S = 5/2. Under anaerobic conditions the absorbance maximum at 600 nm decreases with an exponential decay constant = 0.77 h-1, and the EPR and Mössbauer spectra of Fe3+-adriamycin similarly decrease as the Fe3+ is reduced to EPR silent Fe2+. The Fe2+-adriamycin complex which is formed exhibits a Mössbauer spectrum with delta = 1.18 mm/s and delta EQ = 1.82 mm/s indicative of high spin Fe2+. As the EPR spectra of Fe3+-adriamycin decrease on reduction of the Fe3+ to Fe2+ a signal of the oxidized adriamycin free radical appears at g = 2.004 with line width of 8 G. On exposure to O2 the absorption maximum at 600 nm, the Fe3+ EPR, and the Fe3+ Mössbauer spectra all return. Polarographic measurements demonstrate that O2 is consumed and that H2O2 is formed. Addition of high affinity Fe2+ chelators block O2 consumption indicating that Fe2+ formation is essential for O2 reduction. This cycle of iron-mediated O2 reduction can explain the formation of the reactive reduced oxygen and adriamycin radicals which are thought to mediate the biological activity of adriamycin.
authors.forename: L
authors.initials: L
authors.lastname: Gianni
authors.forename: J L
authors.initials: JL
authors.lastname: Zweier
authors.forename: A
authors.initials: A
authors.lastname: Levy
authors.forename: C E
authors.initials: CE
authors.lastname: Myers
mesh_terms: D002374:Catalase / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D004579:Electron Transport; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000378:metabolism*; D008956:Models, Chemical; D010100:Oxygen / Q000378:metabolism*; D011048:Polarography; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D004317:Doxorubicin; D007501:Iron; D002374:Catalase; D013482:Superoxide Dismutase; D010100:Oxygen