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Carbenoxolone Induces Oxidative Stress in Liver Mitochondria, Which Is Responsible for Transition Pore Opening

Dipartimento di Chimica Biologica (M.S., V.B., A.T.), Università di Padova, Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Unità per lo Studio delle Biomembrane, 35121 Padova; Dipartimento di Scienze Mediche e Chirurgiche-Endocrinologia (C.F., D.A.), Università di Padova, 35129 Padova; and Servizio di Endocrinologia (M.P.), Università di Sassari, 07100 Sassari, Italy

Address all correspondence and requests for reprints to: Professor Antonio Toninello, Dipartimento di Chimica Biologica, Università di Padova, Istituto di Neuroscienze del Consiglio Nazionale delle Ricerche, Unità per lo Studio delle Biomembrane, viale G. Colombo 3, 35121 Padova, Italy. 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 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.

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