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Mitoxantrone and ametantrone inhibit hydroperoxide-dependent initiation and propagation reactions in fatty acid peroxidation.

Publication ,  Journal Article
Kharasch, ED; Novak, RF
Published in: J Biol Chem
September 5, 1985

The anthracenedione antineoplastic agents mitoxantrone and ametantrone are potent inhibitors of basal and drug-stimulated lipid peroxidation in a variety of subcellular systems (Kharasch, E. D., and Novak, R. F. (1983) J. Pharmacol. Exp. Ther. 226, 500-506). The mechanism by which these compounds function as antioxidants has been investigated using enzymic and chemical systems. Mitoxantrone and ametantrone inhibited NADPH-cytochrome P-450 reductase- and xanthine oxidase-catalyzed conjugated diene formation from linoleic acid in a concentration-dependent manner with half-maximal inhibition achieved at approximately 0.5 microM anthracenedione. Inhibition of linoleic acid peroxidation was not attributable to a decrease in P-450 reductase activity, hydroxyl radical scavenging, or iron chelation by the anthracenediones. Nonenzymic fatty acid peroxidation was also inhibited by the anthracenediones. Linoleic acid oxidation initiated by superoxide (ferrous iron autoxidation) or by hydroxyl radicals (Fenton's reagent) was diminished by mitoxantrone and ametantrone after a brief delay, suggesting an effect subsequent to activated oxygen-dependent initiation. In contrast, linoleic acid oxidation initiated by iron-dependent hydroperoxide decomposition was inhibited immediately. Reinitiation of linoleic acid oxidation in an anthracenedione-inhibited system was accomplished only by superoxide generation, but not by fatty acid hydroperoxide decomposition. These results suggest the anthracenediones diminished neither oxygen radical formation nor oxygen radical-dependent initiation of peroxidation. Rather, inhibition of fatty acid peroxidation by mitoxantrone and ametantrone results from the inhibition of hydroperoxide-dependent initiation and propagation reactions.

Duke Scholars

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

September 5, 1985

Volume

260

Issue

19

Start / End Page

10645 / 10652

Location

United States

Related Subject Headings

  • Xanthine Oxidase
  • Spectrophotometry
  • Mitoxantrone
  • Micelles
  • Lipid Peroxides
  • Linoleic Acids
  • Linoleic Acid
  • Kinetics
  • Hydroxyl Radical
  • Hydroxides
 

Citation

APA
Chicago
ICMJE
MLA
NLM

Published In

J Biol Chem

ISSN

0021-9258

Publication Date

September 5, 1985

Volume

260

Issue

19

Start / End Page

10645 / 10652

Location

United States

Related Subject Headings

  • Xanthine Oxidase
  • Spectrophotometry
  • Mitoxantrone
  • Micelles
  • Lipid Peroxides
  • Linoleic Acids
  • Linoleic Acid
  • Kinetics
  • Hydroxyl Radical
  • Hydroxides