The interaction of platinum antitumour drugs with mouse liver mitochondria.
A study was undertaken to determine if cis-DDP and its second generation derivatives produced effects on mouse liver mitochondria, and if any of the observed effects could be correlated with the nephrotoxicity of the drugs. Although changes were observed in mitochondrial morphology, enzyme activity, Ca2+ influx, terbium binding and surface potential, no specific effect was correlated with nephrotoxicity. cis-DDP produced marked changes in mitochondrial morphology; electron probe analysis showed binding of the drug to the mitochondria. Inhibition of complex I and II activity of the respiratory chain and an ionic-strength-dependent effect on Tb3+ (a Ca2+ analogue) fluorescence were observed. The non-nephrotoxic derivatives, CHIP and tetraplatin, also produced significant changes in morphology. Treatment with these derivatives also produced decreases in mitochondrial enzyme activity, but the effect on terbium binding had an ionic-strength dependence which was inverse to that observed with cis-DDP. The tetravalent compounds also had a notable effect on mitochondrial surface potential. Carboplatin had an effect on morphology and Ca2+ influx and it inhibited the respiratory enzymes, although in a manner different from that observed with cis-DDP. Carboplatin had a minimal effect on terbium binding. It is evident that if the platinum drugs enter a cell to exert their action at the nuclear level, they will also depress mitochondrial function. The observed effects did not correlate with nephrotoxicity but, since all four compounds significantly altered mitochondrial structure and function, they may be related to the cytotoxicity of the drug.
Rosen
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Department of Pathology, Staten Island University Hospital, New York 10305.
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D004577:Electron Probe Microanalysis; D008099:Liver / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000648:ultrastructure; D009245:NADH Dehydrogenase / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D006180:Proton-Translocating ATPases / Q000187:drug effects; D013384:Succinate Cytochrome c Oxidoreductase / Q000187:drug effects; D013725:Terbium / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D013725:Terbium; D013384:Succinate Cytochrome c Oxidoreductase; D009245:NADH Dehydrogenase; D006180:Proton-Translocating ATPases; D002945:Cisplatin