Reduction of Bleomycin-Fe by Reductases and Active Oxygen Formation

Abstract

The anticancer drug bleomycin forms a complex with metal ions, e.g. iron ions. Only the reduced complex is able to bind molecular oxygen¹. This “activated bleomycin”² induces DNA strand breaks and malondialdehyde (MDA) formation which originates from the oxidative cleavage of deoxyribose (Fig. 1). “Activated bleomycin” may be formed by low molecular reducing agents¹, but also by enzymatic reduction of bleomycin-Fe(III)^3,4. We wondered whether NADPH- cytochrome P-450 reductase and NADH-cytochrome b₅ reductase are involved in this reduction step. Furthermore, we were interested whether these reductases present in intact cell nuclei are able to catalyze the reduction of bleomycin-Fe(III), the formation of active oxygen and the oxidative cleavage of nuclear DNA. This is important, because DNA damage catalyzed by nuclear reductases may be directly related to cell toxicity induced by bleomycin.