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This version published online on January 27, 2005
Endocrinology, doi:10.1210/en.2004-1128
A more recent version of this article appeared on May 1, 2005
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Submitted on August 25, 2004
Accepted on January 20, 2005

Carbenoxolone induces oxidative stress in liver mitochondria which is responsible for transition pore opening

MAURO SALVI, CRISTINA FIORE, VALENTINA BATTAGLIA, MARIO PALERMO, DECIO ARMANINI, and ANTONIO TONINELLO*

Dipartimento di Chimica Biologica, Università di Padova, Istituto di Neuroscienze del C.N.R., Unità per lo Studio delle Biomembrane, viale G. Colombo 3, 35121 Padova, Italy; Dipartimento di Scienze Mediche e Chirurgiche - Endocrinologia, Università di Padova, via Ospedale 105, 35129 Padova, Italy; Servizio di Endocrinologia -Università di Sassari, via S.Pietro 43, 07100 Sassari, Italy

* To whom correspondence should be addressed. E-mail: antonio.toninello{at}unipd.it.

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 Ca2+ loaded liver mitochondria at 10 µM 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 since 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.
Key words: mitochondria • carbenoxolone • electron transport chain • reactive oxygen species • permeability transition




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