2-Phenyl-beta-lapachone can affect mitochondrial function by redox cycling mediated oxidation.
2-Phenyl-beta-lapachone (3,4-dihydro-2-methyl-2-phenyl-2H-naphtho[1,2b]pyran-5,6-dione) (2PBL) is a o-naphthoquinone synthesized as a possible antitumoral agent. The addition of micromolar concentrations of 2PBL to rat liver mitochondria (in the presence of malate-glutamate or succinate, as respiratory substrates): (1) stimulated O(2) consumption in state 4 and inhibited O(2) consumption in state 3, thus decreasing respiratory control index (RCI); and (2) collapsed the mitochondrial membrane potential. The addition of 2PBL to rat liver submitochondrial particles: (1) stimulated NADH oxidation in the presence of rotenone, antimycin, myxothiazol or cyanide; (2) stimulated (.-)O(2)(-) production in the presence of NADH and antimycin; and (3) led to 2PBL semiquinone radical production. Control studies carried out with two p-naphthoquinones, menadione and atovaquone, did not produced equivalent effects. These findings support the hypothesis that 2PBL, undergoes redox cycling and affects mitochondrial function. The 2PBL effect is complex, involving inhibition of electron transfer, uncoupling of oxidative phosphorylation, collapse of mitochondrial membrane potential and (.-)O(2)(-) production by redox cycling. The mitochondrion could be a target organelle for 2PBL cytotoxicity.
de Witte
Natacha V
NV
Bioenergetics Research Center, School of Medicine, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina.
Stoppani
Andrés O M
AO
Dubin
Marta
M
D000818:Animals; D053626:Atovaquone; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology*; D009285:Naphthoquinones / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D024483:Vitamin K 3 / Q000494:pharmacology
D009285:Naphthoquinones; C014638:beta-lapachone; D024483:Vitamin K 3; D010100:Oxygen; D053626:Atovaquone