The pH-dependent reduction of Adriamycin catalysed by NADH:cytochrome b5 reductase.
Adriamycin is a redox active antineoplastic antibiotic that upon reduction can, in the presence of oxygen, redox cycle to form reactive oxygen species, while in anaerobiosis can generate a reactive quinone methide. NADH:cytochrome b5 reductase catalysed the reduction of adriamycin at pH 6.6 with an apparent Km of 1.8 microM; at pH 7.6, no measurable reduction of adriamycin occurred. Aerobically, in the presence of enzyme and NADH, adriamycin stimulated oxygen consumption and concomitant accumulation of hydrogen peroxide. At pH 7.6, no discernible oxygen consumption nor detectable hydrogen peroxide generation was observed. The findings demonstrate that NADH:cytochrome b5 reductase is capable of reducing adriamycin, in a pH-dependent manner, to species that can redox cycle in the presence of oxygen to form reactive oxygen molecules and thus may contribute to the generation of oxidative stress, a phenomenon suggested to be involved in both the toxicity and the antineoplastic activity of adriamycin.
Hodnick
W F
WF
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
Sartorelli
A C
AC
D003579:Cytochrome Reductases / Q000378:metabolism*; D042966:Cytochrome-B(5) Reductase; D004317:Doxorubicin / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D010101:Oxygen Consumption
D004317:Doxorubicin; D003579:Cytochrome Reductases; D042966:Cytochrome-B(5) Reductase