Mechanism of toxicity of an experimental bidentate phosphine gold complexed antineoplastic agent in isolated rat hepatocytes.
SK&F 104524 (bis-[1,2 bis(diphenylphosphino)-ethane]gold(l) lactate) [( Au(dppe)2]+) is an experimental antineoplastic agent that is hepatotoxic in vivo in the dog as well as highly cytotoxic to isolated canine hepatocytes in vitro. Preliminary studies in isolated dog hepatocytes have indicated that [Au(dppe)2]+ causes an increase in hepatocyte respiration and a decrease in cellular ATP. The purpose of the present investigation was to characterize [Au(dppe)2]+-induced cytotoxicity and biochemical lesions in the intact cell and to correlate these changes with mitochondrial function. The uptake of [14C][Au(dppe)2]+ by rat hepatocytes was rapid, reaching a maximum by 30 min. [Au(dppe)2]+ was distributed throughout the hepatocyte and associated rapidly with mitochondria, nuclei, cytosol and cellular membranes. [Au(dppe)2]+ caused cell lethality in a concentration-dependent fashion; although 5 microM did not cause any changes in lactic dehydrogenase leakage, 20 microM produced 100% cell death by 120 min. [Au(dppe)2]+ also caused concentration-dependent bleb formation of the hepatocyte plasma membrane, increased oxygen consumption and loss of ATP within 30 min. ATP loss was associated with transient increases in AMP and ADP and a profound drop in the ATP/ADP ratio and energy charge. Total nucleotides (adenine and xanthine nucleotides) remained constant. The pattern of glutathione depletion coincided with that of lactic dehydrogenase leakage. Electron microscopy of hepatocytes exposed to [Au(dppe)2]+ for 30 min revealed depletion of glycogen granules and marked swelling of mitochondria. In isolated rat liver mitochondria, [Au(dppe)2]+ caused a stimulation of state 4 respiration and loss of the respiratory control ratio. [Au(dppe)2]+ also relieved the oligomycin-induced inhibition of state 3 (ADP-stimulated) respiration.(ABSTRACT TRUNCATED AT 250 WORDS)
Smith
P F
PF
Department of Investigative Toxicology, Smith Kline and French Laboratories, Pennsylvania.
Hoke
G D
GD
Alberts
D W
DW
Bugelski
P J
PJ
Lupo
S
S
Mirabelli
C K
CK
Rush
G F
GF
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; C050185:bis(1,2-bis(diphenylphosphino)ethane)gold(I); D005978:Glutathione