Ditercalinium, a nucleic acid binder, inhibits the respiratory chain of isolated mammalian mitochondria.
Ditercalinium (a 7H-pyridocarbazole dimer) has been designed to bisintercalate into double-stranded DNA with high affinity. In this paper we provide evidence for inhibitory interactions of ditercalinium with electron transport in isolated rat liver mitochondria. It is shown that ditercalinium probably inhibits the electron transfer between membrane cytochrome c and oxygen (cytochrome c oxidase activity) and the electron transfer between the matrix side of inner membrane (Complexes II and III) and membrane cytochrome c. The level of inhibition of the last oxidation step of the respiratory chain appears to be highly dependent on the drug/membrane diphosphatidylglycerol ratio. It is suggested that the mechanism of cytochrome c oxidase inhibition by ditercalinium could be due to the complexation with the diphosphatidylglycerol environment essential for its activity rather than to a drug-enzyme direct interaction. This hypothesis is strengthened by experiments with pure cytochrome oxidase. Therefore, the interaction of ditercalinium with diphosphatidylglycerol may be envisaged as one factor, among others, responsible for its hepatotoxicity.
Dupont
J
J
Laboratoire de Biochimie et Biologie Cellulaire Végétale, CNRS (URA 1180), Université Pierre et Marie Curie, Paris, France.
Schwaller
M A
MA
Dodin
G
G
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D003580:Cytochromes / Q000378:metabolism*; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism; D007364:Intercalating Agents / Q000494:pharmacology*; D007700:Kinetics; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013816:Thermodynamics
D002227:Carbazoles; D003580:Cytochromes; D007364:Intercalating Agents; D003576:Electron Transport Complex IV; C042804:ditercalinium