The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. III. Chlorotriethylphosphine gold(I)-induced alterations in isolated rat liver mitochondrial function.
Chlorotriethylphosphine gold(I) (TEPAu) is an organo-gold compound that has therapeutic activity in animal models of rheumatoid arthritis. Initial studies have suggested that TEPAu is a potent cytotoxic compound in vitro against a variety of cultured cell types and isolated hepatocytes. Mitochondrial dysfunction induced by this compound has been suggested as a primary biochemical alteration which may result in lethal cell injury in isolated hepatocytes. The purpose of this study was, therefore, to determine the mechanism of TEPAu-induced dysfunction of isolated rat liver mitochondria. TEPAu induced a rapid, concentration-related collapse of the mitochondrial inner membrane potential (EC50 = 24.7 +/- 2.5 microM) which was potentiated in Ca2+ loaded mitochondria (EC50 = 11.3 +/- 3.8 microM). TEPAu-induced collapse of the membrane potential was partially inhibited in the presence of ruthenium red or EGTA. TEPAu caused the rapid release of mitochondrially sequestered Ca2+ which was not inhibited by ruthenium red and, thus, was not via a reversal of the Ca2+ uniporter. TEPAu caused mitochondrial swelling, increased permeability of the inner membrane, and the oxidation/hydrolysis of endogenous mitochondrial pyridine nucleotides. Addition of exogenous ATP slightly reversed the effects of TEPAu on pyridine nucleotides. TEPAu-induced mitochondrial alterations were reversed or inhibited by exposure to the sulfhydryl reducing agent, dithiothreitol. Also, the TEPAu-induced collapse of the mitochondrial membrane potential was partially inhibited by dibucaine, a non-specific inhibitor of phospholipases. These data suggest that TEPAu-induced mitochondrial dysfunction is sulfhydryl dependent. TEPAu-induced mitochondrial dysfunction results in dissipation of the potential difference across the inner mitochondrial membrane which inhibits mitochondrial oxidative phosphorylation. The mechanism by which TEPAu induces the collapse of the membrane potential may be mediated by a sulfhydryl-dependent increase in permeability of the inner membrane to protons.
Hoke
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GD
Smith Kline and French Laboratories, Philadelphia, Pennsylvania 19101.
Rush
G F
GF
Mirabelli
C K
CK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003992:Dibucaine / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010720:Phosphines; D010740:Phospholipases / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D012430:Ruthenium Red / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D010720:Phosphines; D009243:NAD; D012430:Ruthenium Red; C016797:triethyl phosphine gold; D004533:Egtazic Acid; D010740:Phospholipases; D003992:Dibucaine; D002118:Calcium; D004229:Dithiothreitol