Characterization of the cycle of iron-mediated electron transfer from adriamycin to molecular oxygen

L. Gianni, J. L. Zweier, A. Levy, C. E. Myers

Research output: Contribution to journalArticlepeer-review

Abstract

The anticancer drug adriamycin binds iron and these complexes cycle to reduce molecular oxygen. Optical absorption, EPR, and Moessbauer 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 Moessbauer spectrum with isomer shift δ=0.57 mm/s and quadrupole splitting ΔE(Q)=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 Moessbauer spectra of Fe3+-adriamycin similarly decrease as the Fe3+ is reduced to EPR silent Fe2+. The Fe2+-adriamycin complex which is formed exhibits a Moessbauer spectrum with δ=1.18 mm/s and ΔE(Q)=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+ Moessbauer 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.

Original languageEnglish
Pages (from-to)6820-6826
Number of pages7
JournalJournal of Biological Chemistry
Volume260
Issue number11
Publication statusPublished - 1985

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of 'Characterization of the cycle of iron-mediated electron transfer from adriamycin to molecular oxygen'. Together they form a unique fingerprint.

Cite this