title: Protonophoric activity of ellipticine and isomers across the energy-transducing membrane of mitochondria.
abstract: Ellipticine is an antitumor alkaloid capable of uncoupling mitochondrial oxidative phosphorylation. It behaves as a lipophilic weak base with pK = 7.40. We have investigated its molecular mode of action using several of its isomers with pK ranging between 5.8 and 7.7 and ellipticinium, which is a permanent cationic derivative. The effects of these molecules on mitochondrial oxygen uptake and transmembrane potential were compared at different pHs. Ellipticinium exhibited very low effects on both respiratory rate and membrane potential. By contrast, protonable derivatives showed maximal stimulation of oxygen uptake and depolarizing effects when the pH of the medium was close to the drug pK. These effects were lowered when the transmembrane delta pH was dissipated, which indicates that the neutral form of the drug is implicated in the uncoupling mechanism. In addition, protonable derivatives of ellipticine display a linear relationship between oxidation rate and transmembrane potential, which suggests that the uncoupling properties of these molecules result from a protonophoric mechanism. From these results, the following cyclic protonophoric mechanism is proposed for protonable ellipticines: (i) electrophoretical accumulation of the protonated form; (ii) deprotonation at the matrix interface; (iii) diffusion outwards; and (iv) reprotonation at the external interface.
authors.affiliation: Institut de Topologie et Dynamique des Systèmes, CNRS URA 34, Université Paris 7, France.
authors.forename: M A
authors.initials: MA
authors.lastname: Schwaller
authors.forename: B
authors.initials: B
authors.lastname: Allard
authors.forename: E
authors.initials: E
authors.lastname: Lescot
authors.forename: F
authors.initials: F
authors.lastname: Moreau
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004611:Ellipticines / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009550:Nigericin / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004611:Ellipticines; D007476:Ionophores; D014475:Uncoupling Agents; C034192:ellipticine; D009550:Nigericin