Interaction of genistein with the mitochondrial electron transport chain results in opening of the membrane transition pore.
Genistein, a natural isoflavone present in soybeans, is a potent agent in the prophylaxis and treatment of cancer. Addition of genistein to isolated rat liver mitochondria (RLM) induces swelling, loss of membrane potential and release of accumulated Ca2+. These changes are Ca2+-dependent and are prevented by cyclosporin A (CsA) and bongkrekic acid (BKA), two classical inhibitors of the mitochondrial permeability transition (MPT). Induction of the MPT by genistein is accompanied by oxidation of thiol groups and pyridine nucleotides. The reducing agent dithioerythritol and the alkylating agent N-ethylmaleimide (NEM) completely prevent the opening of the transition pore, thereby emphasizing that the effect of the isoflavone correlates with the mitochondrial redox state. Further analyses showed that genistein induces the MPT by the generation of reactive oxygen species (ROS) due to its interaction with the respiratory chain at the level of mitochondrial complex III.
Salvi
Mauro
M
Dipartimento di Chimica Biologica, Istituto di Neuroscienze del C.N.R., Unità per lo Studio delle Biomembrane, Università di Padova, Via G. Colombo 3, 35121, Padova, Italy.
Brunati
Anna Maria
AM
Clari
Giulio
G
Toninello
Antonio
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism*; D001865:Bongkrekic Acid / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D019833:Genistein / Q000378:metabolism*; D007202:Indicators and Reagents / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D014475:Uncoupling Agents; D001865:Bongkrekic Acid; D012430:Ruthenium Red; D004533:Egtazic Acid; D016572:Cyclosporine; D019833:Genistein; D005033:Ethylmaleimide; D004229:Dithiothreitol