title: Acetaminophen stimulates the peroxidative metabolism of anthracyclines.
abstract: Acetaminophen, a common analgesic and antipyretic drug, is frequently administered to individuals undergoing anthracycline chemotherapy. Here, the effect of acetaminophen on the metabolism of daunorubicin and doxorubicin by isolated enzymes lactoperoxidase and myeloperoxidase, and by myeloperoxidase-containing human leukemia HL-60 cells was investigated using spectrophotometric and EPR techniques. We report that at pharmacological concentrations acetaminophen strongly stimulates oxidation of the anthracyclines by lactoperoxidase and myeloperoxidase systems, which results in irreversibly altered (colorless) products. The initial rate and efficacy of daunorubicin oxidation depends on pH. While at pH approximately 7 the oxidation is rapid and extensive, almost no oxidation occurs at pH approximately 5. In the absence of daunorubicin, oxidation of acetaminophen by lactoperoxidase/hydrogen peroxide is only weakly dependent on pH, however, at pH 7.4 it strongly depends on [daunorubicin]. Ascorbate and reduced glutathione strongly inhibited oxidation of anthracyclines by lactoperoxidase and HL-60 systems. Using EPR, a daunorubicin-derived radical was detected in a daunorubicin/acetaminophen/peroxidase/hydrogen peroxide system as a narrow single line (0.175 mT) with g = 2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g = 2.0043, line width approximately 0.5 mT). Similar results were obtained with doxorubicin. We suggest that the stimulation by acetaminophen is primarily due to its preferential oxidation by peroxidases to the corresponding phenoxyl radical, which subsequently reacts with daunorubicin (doxorubicin). Because biological properties of oxidatively transformed anthracyclines will certainly be different from those of their parent compounds, the possible acetaminophen-enhanced degradation of the anthracyclines in vivo is likely to interfere with anticancer and/or cardiotoxic activities of these agents.
authors.affiliation: Research Service, VA Medical Center, Iowa City, IA 52246, USA. reszka@icva.gov
authors.forename: Krzysztof J
authors.initials: KJ
authors.lastname: Reszka
authors.forename: Laura H
authors.initials: LH
authors.lastname: Britigan
authors.forename: George T
authors.initials: GT
authors.lastname: Rasmussen
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Burns
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D003630:Daunorubicin / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D013268:Stimulation, Chemical
chemical_list: D000082:Acetaminophen; D006861:Hydrogen Peroxide; D003630:Daunorubicin