Glycyrrhetinic acid as inhibitor or amplifier of permeability transition in rat heart mitochondria.
Glycyrrhetinic acid (GE), a hydrolysis product of glycyrrhizic acid, one of the main constituents of licorice root, is able, depending on its concentration, to prevent or to induce the mitochondrial permeability transition (MPT) (a phenomenon related to oxidative stress) in rat heart mitochondria (RHM). In RHM, below a threshold concentration of 7.5 microM, GE prevents oxidative stress and MPT induced by supraphysiological Ca2+ concentrations. Above this concentration, GE induces oxidative stress by interacting with a Fe-S centre of Complex I, thus producing ROS, and amplifies the opening of the transition pore, once again induced by Ca2+. GE also inhibits Ca2+ transport in RHM, thereby preventing the oxidative stress induced by the cation. However, the reduced amount of Ca2+ transported in the matrix is sufficient to predispose adenine nucleotide translocase for pore opening. Comparisons between observed results and the effects of GE in rat liver mitochondria (RLM), in which the drug induces only MPT without exhibiting any protective effect, confirm that it interacts in a different way with RHM, suggesting tissue specificity for its action. The concentration dependence of the opposite effects of GE, in RHM but not RLM, is most probably due to the existence of a different, more complex, pathway by means of which GE reaches its target. It follows that high GE concentrations are necessary to stimulate the oxidative stress capable of inducing MPT, because of the above effect, which prevents the interaction of low concentrations of GE with the Fe-S centre. The reported results also explain the mechanism of apoptosis induction by GE in cardiomyocytes.
Battaglia
Valentina
V
Department of Biological Chemistry, University of Padova, CNR Institute of Neurosciences, Padova, Italy.
Brunati
Anna Maria
AM
Fiore
Cristina
C
Rossi
Carlo Alberto
CA
Salvi
Mauro
M
Tibaldi
Elena
E
Palermo
Mario
M
Armanini
Decio
D
Toninello
Antonio
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013438:Sulfhydryl Compounds / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D013438:Sulfhydryl Compounds; D045304:Cytochromes c; D005978:Glutathione; D006034:Glycyrrhetinic Acid; D002118:Calcium