Mechanism of alterations in isolated rat liver mitochondrial function induced by gold complexes of bidentate phosphines.
Au(DPPE)+2 (bis[1,2-bis(diphenylphosphino)ethane] gold(I] is an organo-gold antineoplastic agent that has anti-tumor activity in a variety of in vitro cell lines and in vivo rodent tumor models. Preliminary studies suggested that this compound represented a novel class of inhibitors of mitochondrial function. The purpose of this study was, therefore, to determine the mechanism of mitochondrial dysfunction induced by Au(DPPE)+2. Au(DPPE)+2 induced a rapid, dose-related collapse of the inner mitochondrial membrane potential (EC50 = 28.0 microM) that was not potentiated by Ca2+ preloading. Au(DPPE)+2-induced dissipation of mitochondrial membrane potential was accompanied by an efflux of Ca2+ from mitochondria upon exposure to Au(DPPE)+2. Ca2+ efflux in these experiments was via a reversal of the Ca2+ uniporter as efflux could be inhibited with ruthenium red. Au(DPPE)+2 did not increase the permeability of mitochondria to oxalacetate, indicating that the collapse of membrane potential may not be a result of gross increased inner membrane permeability. However, Au(DPPE)+2 may mediate an increased permeability of the inner membrane to cations and protons. Au(DPPE)+2 caused passive swelling in potassium acetate buffer in the absence of valinomycin, suggesting Au(DPPE)+2 facilitated the exchange of H+ and K+. Ca2+ cycling was not extensive and did not contribute to the decrease in membrane potential. These data suggest that one possible mechanism of Au(DPPE+2-induced uncoupling of mitochondrial oxidative phosphorylation is via increased permeability of the inner mitochondrial membrane to cations. The disruption of mitochondrial function may be a key process leading to hepatocyte cell injury by this drug.
Hoke
G D
GD
SmithKline and French Laboratories, Philadelphia, Pennsylvania 19101.
Rush
G F
GF
Bossard
G F
GF
McArdle
J V
JV
Jensen
B D
BD
Mirabelli
C K
CK
D000085:Acetates / Q000378:metabolism; D019342:Acetic Acid; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects*; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010101:Oxygen Consumption; D010539:Permeability; D051381:Rats; D012430:Ruthenium Red / Q000378:metabolism; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid
D000085:Acetates; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D013386:Succinates; D012430:Ruthenium Red; C050185:bis(1,2-bis(diphenylphosphino)ethane)gold(I); D019802:Succinic Acid; D019342:Acetic Acid; D002118:Calcium