Acetaminophen stimulates the peroxidative metabolism of anthracyclines

Krzysztof J. Reszka, Laura H. Britigan, George T. Rasmussen, Brett A. Wagner, C. Patrick Burns, Bradley E. Britigan

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 ∼7 the oxidation is rapid and extensive, almost no oxidation occurs at pH ∼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 (0.175mT) with g=2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g=2.0043, line width ∼0.5mT). 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.

Original languageEnglish (US)
Pages (from-to)16-29
Number of pages14
JournalArchives of Biochemistry and Biophysics
Volume427
Issue number1
DOIs
StatePublished - Jul 1 2004

Fingerprint

Daunorubicin
Anthracyclines
Acetaminophen
Metabolism
Lactoperoxidase
Oxidation
Peroxidase
Doxorubicin
Paramagnetic resonance
Hydrogen Peroxide
Cardiotoxins
Peroxidases
Antipyretics
Chemotherapy
HL-60 Cells
Melanins
Linewidth
Glutathione
Analgesics
Leukemia

Keywords

  • Acetaminophen
  • Anthracyclines
  • Ascorbate
  • Daunorubicin
  • Doxorubicin
  • EPR
  • Free radicals
  • Lactoperoxidase
  • Myeloperoxidase
  • Peroxidative metabolism
  • Reduced gluathione

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Acetaminophen stimulates the peroxidative metabolism of anthracyclines. / Reszka, Krzysztof J.; Britigan, Laura H.; Rasmussen, George T.; Wagner, Brett A.; Burns, C. Patrick; Britigan, Bradley E.

In: Archives of Biochemistry and Biophysics, Vol. 427, No. 1, 01.07.2004, p. 16-29.

Research output: Contribution to journalArticle

Reszka, Krzysztof J. ; Britigan, Laura H. ; Rasmussen, George T. ; Wagner, Brett A. ; Burns, C. Patrick ; Britigan, Bradley E. / Acetaminophen stimulates the peroxidative metabolism of anthracyclines. In: Archives of Biochemistry and Biophysics. 2004 ; Vol. 427, No. 1. pp. 16-29.
@article{abbcbbed683441daa0f948f5a5a97cad,
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 ∼7 the oxidation is rapid and extensive, almost no oxidation occurs at pH ∼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 (0.175mT) with g=2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g=2.0043, line width ∼0.5mT). 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.",
keywords = "Acetaminophen, Anthracyclines, Ascorbate, Daunorubicin, Doxorubicin, EPR, Free radicals, Lactoperoxidase, Myeloperoxidase, Peroxidative metabolism, Reduced gluathione",
author = "Reszka, {Krzysztof J.} and Britigan, {Laura H.} and Rasmussen, {George T.} and Wagner, {Brett A.} and Burns, {C. Patrick} and Britigan, {Bradley E.}",
year = "2004",
month = "7",
day = "1",
doi = "10.1016/j.abb.2004.04.012",
language = "English (US)",
volume = "427",
pages = "16--29",
journal = "Archives of Biochemistry and Biophysics",
issn = "0003-9861",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Acetaminophen stimulates the peroxidative metabolism of anthracyclines

AU - Reszka, Krzysztof J.

AU - Britigan, Laura H.

AU - Rasmussen, George T.

AU - Wagner, Brett A.

AU - Burns, C. Patrick

AU - Britigan, Bradley E.

PY - 2004/7/1

Y1 - 2004/7/1

N2 - 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 ∼7 the oxidation is rapid and extensive, almost no oxidation occurs at pH ∼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 (0.175mT) with g=2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g=2.0043, line width ∼0.5mT). 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.

AB - 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 ∼7 the oxidation is rapid and extensive, almost no oxidation occurs at pH ∼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 (0.175mT) with g=2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g=2.0043, line width ∼0.5mT). 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.

KW - Acetaminophen

KW - Anthracyclines

KW - Ascorbate

KW - Daunorubicin

KW - Doxorubicin

KW - EPR

KW - Free radicals

KW - Lactoperoxidase

KW - Myeloperoxidase

KW - Peroxidative metabolism

KW - Reduced gluathione

UR - http://www.scopus.com/inward/record.url?scp=2642539988&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2642539988&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2004.04.012

DO - 10.1016/j.abb.2004.04.012

M3 - Article

C2 - 15178484

AN - SCOPUS:2642539988

VL - 427

SP - 16

EP - 29

JO - Archives of Biochemistry and Biophysics

JF - Archives of Biochemistry and Biophysics

SN - 0003-9861

IS - 1

ER -