Scavenging effects of dexrazoxane on free radicals

Zhang Junjing, Zhao Yan, Zhao Baolu, Zhang Junjing, Zhao Yan, Zhao Baolu

Abstract

Dexrazoxane (ICRF-187) has been clinically used to reduce doxorubicin-induced cardiotoxicity for more than 20 years. It has been proposed that dexrazoxane may act through its rings-opened hydrolysis product ADR-925, which can either remove iron from the iron-doxorubicin complex or bind to free iron, thus preventing iron-based oxygen radical formation. However, it is not known whether the antioxidant actions of dexrazoxane are totally dependent on its metabolization to its rings-opened hydrolysis product and whether dexrazoxane has any effect on the iron-independent oxygen free radical production. In this study, we examined the scavenging effect of dexrazoxane on hydroxyl, superoxide, lipid, DPPH and ABTS(+) free radicals in vitro solution systems. The results demonstrated that dexrazoxane was an antioxidant that could effectively scavenge these free radicals and the scavenging effects of dexrazoxane did not require the enzymatic hydrolysis. In addition, dexrazoxane was capable to inhibit the generation superoxide and hydroxyl radicals in iron free reaction system, indicating that the antioxidant properties of dexrazoxane were not solely dependent on iron chelation. Thus the application of dexrazoxane should not be limited to doxorubicin-induced cardiotoxicity. Instead, as an effective antioxidant that has been clinically proven safe, dexrazoxane may be used in a broader spectrum of diseases that are known to be benefited by antioxidant treatments.

Keywords: antioxidant; dexrazoxane; free radical scavenger; ion-chelater; oxygen free radicals.

Figures

Fig. 1
Fig. 1
a. A reaction scheme for the hydrolysis of dexrazoxane to metabolites B and C and its strong metal ion-chelating form ADR-925; b. DHOase-catalyzed reversible conversion of L-dihydroorotate into N-carbamoyl-L-aspartate (carbamyl aspartate).
Fig. 2
Fig. 2
Scavenging effects of dexrazoxane on superoxide free radicals. Superoxide free radicals were generated from irradiation of riboflavin and spin trapped by DMPO. (The ESR spectrum is shown in the inset). Different concentrations of dexrazoxane were added to the reaction mixture and the generation of superoxide free radicals was determined by ESR spectroscopy. Details of the procedure are described in the “Materials and Methods” (n = 6).
Fig. 3
Fig. 3
Scavenging effects of dexrazoxane on hydroxyl free radicals generated from photolysis of H2O2. The inset shows the ESR spectrum of hydroxyl free radicals spin trapped by DMPO. Details of the procedure are described in the “Materials and Methods” (n = 6).
Fig. 4
Fig. 4
Scavenging effects of dexrazoxane on hydroxyl free radicals generated from Fenton reaction. The inset shows the ESR spectrum of DMPO-OH. Details of the procedure are described in the “Materials and Methods” (n = 6).
Fig. 5
Fig. 5
Scavenging effects of dexrazoxane on lipid free radicals generated from lipid peroxidation of mitochondria. The inset shows the ESR spectrum of lipid free radicals generated from lipid peroxidation of mitochondria induced by photolysis of H2O2 and spin trapped by 4-POBN. Details of the procedure are described in the “Materials and Methods” (n = 6).
Fig. 6
Fig. 6
Scavenging effects dexrazoxane on DPPH free radical. The inset shows the ESR spectrum of DPPH free radicals. Different concentrations of dexrazoxane were added to the DPPH free radical solution and analysed by ESR spectroscopy. Details of the procedure are described in the “Materials and Methods” (n = 6).
Fig. 7
Fig. 7
Scavenging effects of dexrazoxane on ABTS+ cation free radical. Different concentrations of dexrazoxane were added to the ABTS+ working solution and measured at 734 nm by spectrophotometer. Details of the procedure are described in the “Materials and Methods” (n = 6).

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