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Mitoxantrone and ametantrone inhibit hydroperoxide-dependent initiation and propagation reactions in fatty acid
Abstract:
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.
Insights
Mitoxantrone and ametantrone, anthracenedione antineoplastic agents, inhibit lipid peroxidation by blocking hydroperoxide-dependent reactions. These antioxidants do not affect oxygen radical formation or initiation pathways.
Area of Science:
- Biochemistry
- Pharmacology
- Antioxidant research
Background:
- Lipid peroxidation is a damaging process implicated in various diseases.
- Anthracenedione antineoplastic agents, such as mitoxantrone and ametantrone, are known to possess antioxidant properties.
Purpose of the Study:
- To investigate the mechanism by which mitoxantrone and ametantrone inhibit lipid peroxidation.
- To determine if these agents scavenge oxygen radicals or interfere with peroxidation initiation.
Main Methods:
- Utilized enzymic and chemical systems to study lipid peroxidation.
- Assessed the effect of mitoxantrone and ametantrone on linoleic acid peroxidation catalyzed by NADPH-cytochrome P-450 reductase and xanthine oxidase.
- Investigated the impact of these agents on peroxidation initiated by superoxide and hydroxyl radicals, as well as by hydroperoxide decomposition.
Main Results:
- Mitoxantrone and ametantrone inhibited both basal and drug-stimulated lipid peroxidation in a concentration-dependent manner.
- Inhibition occurred at approximately 0.5 microM anthracenedione.
- The compounds did not decrease P-450 reductase activity, scavenge hydroxyl radicals, or chelate iron.
- Inhibition of peroxidation initiated by hydroperoxide decomposition was immediate, while inhibition of superoxide or hydroxyl radical-initiated peroxidation was delayed.
- Reinitiation of peroxidation was only achieved by superoxide generation, not hydroperoxide decomposition.
Conclusions:
- Mitoxantrone and ametantrone inhibit lipid peroxidation by interfering with hydroperoxide-dependent initiation and propagation reactions.
- These anthracenediones do not diminish oxygen radical formation or oxygen radical-dependent initiation of peroxidation.
- The findings elucidate a specific antioxidant mechanism for these antineoplastic agents.