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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Oxidation of Anthracyclines by Peroxidase Metabolites of Salicylic Acid

Research Service, Veterans Administration Medical Center, Iowa City, Iowa (K.J.R., L.H.B.); Free Radical and Radiation Biology Program of the Department of Radiation Oncology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa (K.J.R.); Research Service and Department of Internal Medicine, Veterans Administration Medical Center, Cincinnati, Ohio (B.E.B., K.J.R.); and Departments of Internal Medicine (B.E.B., K.J.R.) and Biochemistry, Molecular Genetics and Microbiology (B.E.B.), University of Cincinnati, Cincinnati, Ohio

Oxidation of anthracyclines leads to their degradation and inactivation. This process is carried out by peroxidases in the presence of a catalytic cofactor, a good peroxidase substrate. Here, we investigated the effect of salicylic acid, a commonly used anti-inflammatory and analgesic agent, on the peroxidative metabolism of anthracyclines. We report that at pharmacologically relevant concentrations, salicylic acid stimulates oxidation of daunorubicin and doxorubicin by myeloperoxidase and lactoperoxidase systems and that efficacy of the process increases markedly on changing the pH from 7 to 5. This pH dependence is positively correlated with the ease with which salicylic acid itself undergoes metabolic oxidation and involves the neutral form of the acid (pK_a = 2.98). When salicylic acid reacted with a peroxidase and H₂O₂ at acid pH (anthracyclines omitted), a new metabolite with absorption maximum at 412 nm was formed. This metabolite reacted with anthracyclines causing their oxidation. It was tentatively assigned to biphenyl quinone, formed by oxidation of biphenol produced by dimerization of salicylic acid-derived phenoxyl radicals. The formation of this product was inhibited in a concentration-dependent manner by the anthracyclines, suggesting their scavenging of the salicylate phenoxyl radicals. Altogether, this study demonstrates that oxidation of anthracyclines is mediated by peroxidase metabolites of salicylic acid, such as phenoxyl radicals and the biphenol quinone. Given that cancer patients undergoing anthracycline chemotherapy may be administered salicylic acid-based drugs to control pain and fever, our results suggest that liberated salicylic acid could interfere with anticancer and/or cardiotoxic actions of the anthracyclines.

Address correspondence to: Dr. Krzysztof J. Reszka, Department of Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, ML 0557, Cincinnati, OH 45267-0557. E-mail: reszkakj{at}ucmail.uc.edu