Kinetics of cyclosporine A-induced inhibition of succinate-coenzyme Q dehydrogenase in rat renal cortical mitochondria.
The kinetic mechanism of succinate-coenzyme Q dehydrogenase (Complex II) inhibition by cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS showed two modes of inhibition of Complex II of the mitochondrial electron transport system: (a) a mixed linear noncompetitive inhibition of resting succinate-limited and ADP-stimulated respirations suggesting that CS binds to Complex II at a different site than the substrate, affecting the dissociation constant for the enzyme-substrate complex and (b) a competitive inhibition of the DNP-stimulated electron transport system suggesting competition with the oxidized form of a component of Complex II. CS action to renal mitochondrial Complex II limits its function, an effect which may be related to CS nephrotoxicity.
Lemmi
C A
CA
Department of Anatomy and Cell Biology, UCLA 90024.
Pelikan
P C
PC
Geesaman
B
B
Seamon
E
E
Koyle
M
M
Rajfer
J
J
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D042963:Electron Transport Complex II; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*
D003524:Cyclosporins; D009097:Multienzyme Complexes; D000244:Adenosine Diphosphate; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase