Oxidation of anthracyclines by peroxidase metabolites of salicylic acid

Krzysztof J. Reszka, Laura H. Britigan, Bradley E. Britigan

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 (pKa = 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.

Original languageEnglish (US)
Pages (from-to)283-290
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume315
Issue number1
DOIs
StatePublished - Oct 1 2005

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Salicylic Acid
Anthracyclines
Peroxidase
Lactoperoxidase
Peroxidases
Daunorubicin
Acids
Salicylates
Drug and Narcotic Control
Dimerization
Non-Steroidal Anti-Inflammatory Agents
Doxorubicin
Analgesics
Anti-Inflammatory Agents
Fever
Drug Therapy
Pain

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Oxidation of anthracyclines by peroxidase metabolites of salicylic acid. / Reszka, Krzysztof J.; Britigan, Laura H.; Britigan, Bradley E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 315, No. 1, 01.10.2005, p. 283-290.

Research output: Contribution to journalArticle

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