Carbenoxolone induces oxidative stress in liver mitochondria, which is responsible for transition pore opening.
Carbenoxolone (Cbx), a derivative of glycyrrhetinic acid, which has been found to affect mineralocorticoid and glucocorticoid receptors, induces swelling and membrane potential collapse when added to Ca(2+)-loaded liver mitochondria at 10 microM concentrations. These effects are strictly correlated with hydrogen peroxide generation, increase in oxygen uptake, and sulfhydryl and pyridine nucleotide oxidation. Cyclosporin A, bongkrekic acid, and N-ethylmaleimide completely abolish all the above-described effects, suggesting that Cbx can be considered an inducer of mitochondrial permeability transition by means of oxidative stress. Cbx can also trigger the apoptotic pathway because the above events are also correlated with the loss of cytochrome c. These effects are probably related to the conjugated carbonyl oxygen in C-11, which produces reactive oxygen species by interacting with the mitochondrial respiratory chain, mainly at the level of complex I but, most likely, also with complex III. The oxidative stress induced by Cbx, which is responsible for pore opening, excludes that this is related to a genomic effect of the compound.
Salvi
Mauro
M
Dipartimento di Chimica Biologica, Università di Padova, Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Unità per lo Studio delle Biomembrane, 35121 Padova, Italy.
Fiore
Cristina
C
Battaglia
Valentina
V
Palermo
Mario
M
Armanini
Decio
D
Toninello
Antonio
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002229:Carbenoxolone / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D004579:Electron Transport; D042967:Electron Transport Complex I / Q000737:chemistry; D042963:Electron Transport Complex II / Q000737:chemistry; D014450:Electron Transport Complex III / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010539:Permeability; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D013438:Sulfhydryl Compounds; D012430:Ruthenium Red; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D002229:Carbenoxolone; D001205:Ascorbic Acid; D002118:Calcium