NADPH-cytochrome-P450 reductase promotes hydroxyl radical production by the iron complex of ADR-925, the hydrolysis product of ICRF-187 (dexrazoxane).
ICRF-187 (dexrazoxane) is currently in clinical trials as a cardioprotective agent for the prevention of doxorubicin-induced cardiotoxicity. ICRF-187 likely acts through its strongly metal ion-binding rings-opened hydrolysis product ADR-925 by removing iron from its complex with doxorubicin or by chelating free iron. The ability of NADPH-cytochrome-P450 reductase to promote hydroxyl radical formation by iron complexes of ADR-925 and EDTA was compared by EPR spin trapping. The iron-EDTA complex produced hydroxyl radicals at six times the rate that the iron-ADR-925 complex did. The aerobic oxidation of ferrous complexes of ADR-925, its tetraacid analog, EDTA and DTPA was followed spectrophotometrically. The iron(II)-ADR-925 complex was aerobically oxidized 700 times slower than was the EDTA complex. It is concluded that even though ADR-925 does not completely eliminate iron-based hydroxyl radical production, it likely protects by preventing site-specific hydroxyl radical damage by the iron-doxorubicin complex.
Hasinoff
B B
BB
Faculty of Pharmacy, University of Manitoba Winnipeg, Canada.
D000818:Animals; D002374:Catalase / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism*; D004492:Edetic Acid / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005029:Ethylenediamines / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism*; D008956:Models, Chemical; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011929:Razoxane / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet
D002614:Chelating Agents; D005029:Ethylenediamines; D007502:Iron Chelating Agents; D017665:Hydroxyl Radical; D011929:Razoxane; C059866:ICRF 198; D004492:Edetic Acid; D002374:Catalase; D009251:NADPH-Ferrihemoprotein Reductase; D005998:Glycine