Differential Ability of Cytostatics From Anthraquinone Group to Generate Free Radicals in Three Enzymatic Systems: NADH Dehydrogenase, NADPH Cytochrome P450 Reductase, and Xanthine Oxidase
Abstract:The antitumor drugs of the anthraquinone group are widely used agents in the treatment of a variety of human neoplasms. However, their clinical effectiveness is limited by several factors, among which dose-dependent cardiotoxicity is of great importance. Numerous data indicate that the cardiac effects of these drugs are the consequence of one-electron transfer from reduced nucleotides to atmospheric oxygen. This process is catalyzed primarily by NADH dehydrogenase, NADPH cytochrome P450 reductase, and xanthine oxidase, and leads to the formation of reactive oxygen species. In our previous studies we have shown that the NADH dehydrogenase catalyzed electron transfer phenomenon is correlated with the affinity of anthraquinone drugs to the enzyme. In this work data are presented on the ability of compounds belonging to several structural types of anthraquinone cytostatics (sugar- and quinone-modified derivatives of DR and ADR, and anthracenedione compounds) to stimulate free radical formation in the above three enzymatic systems. It has been shown that the three oxidoreductases exhibit different structural requirements with respect to their substrate properties for anthraquinones. Therefore, evaluation of the structural factors determining the ability of anthraquinone compounds to generate active oxygen species cannot be limited to a single oxidoreductase system but must include all types of enzymatic systems involved in the catalysis of one-electron transfer reactions.
Document Type: Research Article
Affiliations: 1: *Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, Narutowicza St 11/12, 80-952 Gdansk, Poland 2: †Imperial Cancer Research Fund Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK
Publication date: January 1, 2003
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