Uncoupling effects of local anesthetics on rat liver mitochondria

Dabadie, P.; Bendriss, P.; Erny, P.; Mazat, Jean‐Pierre

doi:10.1016/0014-5793(87)80554-9

Cited by 84 publications

(44 citation statements)

References 6 publications

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“…This is due both to the intrinsic interest of clarifying the mechanisms of uncoupling by hydrophobic amines, which are largely used as anesthetics, and to an effort to understand the basis of bupivacaine toxicity (49,50), which is exploited to induce cell death in studies of muscle regeneration (1,2). Despite initial controversies, it now appears established that bupivacaine is a bona fide protonophore (8), although it can also form ion pairs with lipophilic anions (11,48). Because we discovered that bupivacaine can induce the PTP both in isolated mitochondria and intact muscle fibers, it was essential to preliminarily reinvestigate the effects of bupivacaine on mitochondrial energy metabolism under conditions where a contribution of the PTP itself could be excluded, a question that had not been addressed in previous studies on the mechanisms of uncoupling by bupivacaine.…”

Section: Multiple Effects Of Bupivacaine On Mitochondrial Energymentioning

confidence: 99%

Bupivacaine Myotoxicity Is Mediated by Mitochondria

Irwin

Fontaine

Agnolucci

et al. 2002

Journal of Biological Chemistry

162

114

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We have investigated the effects of the myotoxic local anesthetic bupivacaine on rat skeletal muscle mitochondria and isolated myofibers from flexor digitorum brevis, extensor digitorum longus, soleus, and from the proximal, striated portion of the esophagus. In isolated mitochondria, bupivacaine caused a concentration-dependent mitochondrial depolarization and pyridine nucleotide oxidation, which were matched by an increased oxygen consumption at bupivacaine concentrations of 1.5 mM or less at pH 7.4, whereas respiration was inhibited at higher concentrations. As a consequence of depolarization, bupivacaine caused the opening of the permeability transition pore (PTP), a cyclosporin A-sensitive inner membrane channel that plays a key role in many forms of cell death. In intact flexor digitorum brevis fibers bupivacaine caused mitochondrial depolarization and pyridine nucleotides oxidation that were matched by increased concentrations of cytosolic free Ca 2؉ , release of cytochrome c, and eventually, hypercontracture. Both mitochondrial depolarization and cytochrome c release were inhibited by cyclosporin A, indicating that PTP opening rather than bupivacaine as such was responsible for these events. Similar responses to bupivacaine were observed in the soleus, which is highly oxidative. In contrast, fibers from the esophagus (which we show to be more fatigable than flexor digitorum brevis fibers) and from the highly glycolytic extensor digitorum longus didn't undergo pyridine nucleotide oxidation upon the addition of bupivacaine and were resistant to bupivacaine toxicity. These results suggest that active oxidative metabolism is a key determinant in bupivacaine toxicity, that bupivacaine myotoxicity is a relevant model of mitochondrial dysfunction involving the PTP and Ca 2؉ dysregulation, and that it represents a promising system to test new PTP inhibitors that may prove relevant in spontaneous myopathies where mitochondria have long been suspected to play a role.

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Section: Multiple Effects Of Bupivacaine On Mitochondrial Energymentioning

confidence: 99%

Bupivacaine Myotoxicity Is Mediated by Mitochondria

Irwin

Fontaine

Agnolucci

et al. 2002

Journal of Biological Chemistry

162

114

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“…anaesthetics, can also act to uncouple oxidative phosphorylation via the mechanism outlined above without the need to complex with a lipophilic anion. 49 The presence, and pKa, of the tertiary amine group is thought to be responsible for the ability of these chemicals to scavenge protons within the inner membrane space. Therefore, the lack of a tertiary amine group offers an explanation as to why no mitochondrial toxicity has been associated with tocainide.…”

Section: Mechanistic Hypothesis and The Development Of Alertsmentioning

confidence: 99%

Development of an in Silico Profiler for Mitochondrial Toxicity

Nelms

Mellor

Cronin

et al. 2015

Chem. Res. Toxicol.

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This study outlines the analysis of mitochondrial toxicity for a variety of pharmaceutical drugs extracted from Zhang et al. These chemicals were grouped into categories based upon structural similarity. Subsequently, mechanistic analysis was undertaken for each category to identify the Molecular Initiating Event driving mitochondrial toxicity. The mechanistic information elucidated during the analysis enabled mechanism-based structural alerts to be developed and combined together to form an in silico profiler. This profiler is envisaged to be used to develop chemical categories based upon similar mechanisms as part of the Adverse Outcome Pathway paradigm. Additionally, the profiler could be utilised in screening large dataset in order to identify chemicals with the potential to induce mitochondrial toxicity.

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“…In fact, their uncouplinglike activity can be observed only in the presence of exogenously added P i (21)(22)(23). Another class of basic, cationic compounds with lipophilic properties, such as local anesthetics, have been found to display an uncoupling activity, even in the absence of P i (24). Their uncoupling properties were initially attributed (24) to a protonophoric mechanism, which is summarized in Fig.…”

Section: Discussionmentioning

confidence: 99%

Protonophoric Activity of Ellipticine and Isomers across the Energy-transducing Membrane of Mitochondria

Schwaller

Allard

Lescot

et al. 1995

Journal of Biological Chemistry

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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 ⌬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.

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Uncoupling effects of local anesthetics on rat liver mitochondria

Cited by 84 publications

References 6 publications

Bupivacaine Myotoxicity Is Mediated by Mitochondria

Bupivacaine Myotoxicity Is Mediated by Mitochondria

Development of an in Silico Profiler for Mitochondrial Toxicity

Protonophoric Activity of Ellipticine and Isomers across the Energy-transducing Membrane of Mitochondria

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