Reactions of Adriamycin with haemoglobin. Superoxide dismutase indirectly inhibits reactions of the Adriamycin semiquinone

Abstract

The adriamycin semiquinone produced by the reaction of xanthine oxidase and xanthine with [the antineoplastic drug] adriamycin reduces both methemoglobin and cytochrome c. In air, but not N2, both reactions were inhibited by superoxide dismutase. With cytochrome c, superoxide formed by the rapid reaction of the semiquinone with O2 was responsible for the reduction. However, even in air, methemoglobin was reduced directly by the adriamycin semiquinone. Superoxide dismutase inhibited this reaction by removing superoxide and hence the semiquinone by displacing the following equilibrium to the right: Semiquinone + O2 .dblarw. quinone + O2-. This ability to inhibit indirectly reactions of the semiquinone could have wider implications for the protection given by superoxide dismutase against the cytotoxicity of adriamycin. Oxidation of Hb by adriamycin was initiated by a reversible reaction between the drug and oxyhemoglobin, producing methemoglobin and the adriamycin semiquinone. Reaction of the semiquinone with O2 gives superoxide and H2O2, which can also react with Hb. Catalase, by preventing this reaction of H2O2, inhibits oxidation of oxyhemoglobin. Superoxide dismutase accelerates oxidation by inhibiting the reaction of the semiquinone with methemoglobin by the mechanism described above. Although superoxide dismutase has a detrimental effect on Hb oxidation, it may protect the [vertebrate] red [blood] cell against more damaging reactions of the adriamycin semiquinone.