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2-Phenyl-beta-lapachone can affect mitochondrial function by redox cycling mediated oxidation
Natacha V de Witte1, Andrés O M Stoppani, Marta Dubin
1Bioenergetics Research Center, School of Medicine, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina.
Archives of Biochemistry and Biophysics
|November 16, 2004
Summary
2-Phenyl-beta-lapachone (2PBL), an antitumoral agent, disrupts mitochondrial function by affecting electron transfer and membrane potential. This naphthoquinone induces O(2) consumption and radical production, suggesting mitochondria as a cytotoxicity target.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- 2-Phenyl-beta-lapachone (2PBL) is an o-naphthoquinone investigated for potential antitumoral properties.
- Mitochondrial dysfunction is implicated in various diseases, including cancer.
Purpose of the Study:
- To investigate the effects of 2PBL on mitochondrial function and explore its potential as a cytotoxic agent targeting mitochondria.
Main Methods:
- Assessed mitochondrial respiration (State 3 and State 4) and respiratory control index (RCI) in rat liver mitochondria.
- Measured mitochondrial membrane potential collapse.
- Examined NADH oxidation and superoxide radical (O(2)(-)) production in submitochondrial particles.
- Investigated 2PBL semiquinone radical formation.
Main Results:
- 2PBL stimulated State 4 and inhibited State 3 respiration, decreasing RCI.
- 2PBL collapsed mitochondrial membrane potential.
- 2PBL stimulated NADH oxidation and O(2)(-) production, with evidence of semiquinone radical formation.
- Comparative studies with menadione and atovaquone showed distinct effects for 2PBL.
Conclusions:
- 2PBL affects mitochondrial function through redox cycling, inhibiting electron transfer and uncoupling oxidative phosphorylation.
- The observed mitochondrial disruption, including membrane potential collapse and O(2)(-) production, supports the hypothesis that mitochondria are a key target for 2PBL cytotoxicity.