Mitochondrial uncoupling agents
Tóm tắt
Agents which uncouple oxidative phosphorylation in mitochondria were applied to identified neurons in an isolated ganglion of the marine molluscNavanax inermis. Aromatic monocarboxylic acids, acetanilides, benzamides, benzaldehydes and phenols all caused a rapid, reversible, dose-dependent increase in the membrane potential and conductance of the neurons tested. These events were due primarily to an increase in the membrane's conductance to potassium, relative to chloride. All active compounds also produced a reversible, dose-dependent decrease in the permeability of alkali-cations relative to potassium. The relative activity of congeners in each group of substances was directly correlated with the octanol-water partition coefficients of the various compounds, indicating that hydrophobicity was important in determining drug effect and suggesting that steric requirements were minimal. The results suggest that the observed changes in membrane electrical properties and cation selectivity are due to an increase in the membrane's anionic field strength caused by the hydrophobic interaction of anionic and nonionic agents with the neuronal membrane.
Tài liệu tham khảo
Barker, J.L., Levitan, H. 1971. Salicylate: Effects on membrane permeability of molluscan neurons.Science 172:1245
Barker, J.L., Levitan, H. 1974. Phenols: Effects on invertebrate membrane permeability related to uncoupling activity in mitochondria.Brain Res. 67:555
Barker, J.L., Levitan, H. 1975. Acetanilides: Effects on invertebrate neurons correlated with analgesic activity in vertebrates.J. Pharmacol. Exp. Ther. 193:892
Bryant, S.H., Morales-Aguilera, O. 1971. Chloride conductance in normal and mytonic muscle fibres and the action of monocarboxylic aromatic acids.J. Physiol. (Lond.) 219:367
Caswell, A.H. 1969. Proton permeability and the regulation of potassium permeability in mitochondria by uncoupling agents.J. Membrane Biol. 1:53
Diamond, J.M., Wright, E.M. 1969. Biological membranes: The physical basis of ion and nonelectrolyte selectivity.Annu. Rev. Physiol. 31:581
Eisenman, G. 1961. On the elementary atomic origin of equilibrium ion specificity.In: Symposium on Membrane Transport and Metabolism. A. Kleinzeller and K.A. Kotyk, editors. p. 163. Academic Press, New York
Eisenman, G. 1963. The influence of Na, K, Li, Rb, and Cs on cellular potentials and related phenomena.Bol. Inst. Estud. Med. Bio. (Univ. Nac. Auton. Mex.) 21:155
Eisenman, G. Some elementary factors involved in specific ion permeation.Proc. 23rd Int. Cong. Physiol. Sci. (Tokyo), p. 489
Fujita, T. 1966. The analysis of physiological activity of substituted phenols with substituent constants.J. Med. Chem. 9:797
Fujita, T., Iwasa, J., Hansch, C. 1964. A new substituent, constant, π, derived from partition coefficients.J. Amer. Chem. Soc. 86:5175
Godfraind, J.M., Kawamura, H., Krnjević, K., Pumain, R. 1971. Actions of dinitrophenol and some other metabolic inhibitors on cortical neurones.J. Physiol. (London) 215:199
Gorman, A.L.F., McReynolds, J.S. 1974. COntrol of membrane K+ permeability in a hyperpolarizing photoreceptor: Similar effects of light and metabolic inhibitors.Science 185:620
Haas, H.G., Kern, R., Einwächter, H.M. 1970. Electrical activity and metabolism in cardiac tissue: An experimental and theoretical study.J. Membrane Biol. 3:180
Hagiwara, S., Toyama, K., Hayashi, H. 1971. Mechanism of anion and cation permeations in the resting membrane of a barnacle muscle fiber.J. Gen. Physiol. 57:408
Hansch, C. 1971. Quantitative structure-activity relationships in drug design.In: Drug Design. E.J. Ariens, editor. Vol. 1, p. 271. Academic Press, New York
Hansch, C. 1975. Biosterism. Intra-Science Chem. Reports (in press)
Hansch, C., Anderson, S. 1967 The effect of intramolecular hydrophobic bonding on partition coefficients.J. Org. Chem. 32:2583
Hansch, C., Glave, W.R. 1971. Structure-activity relationships in membrane-perturbing agents.Mol. Pharmacol. 7:337
Hansch, C., Helmer, F. 1968. Extrathermodynamic approach to the study of the adsorption of organic compounds by macromolecules.J. Polymer Sci.: Part A-1 6:3295
Hansch, G., Kiehs, K., Lawrence, G.L. 1965. The role of substituents in the hydrophobic bonding of phenols by serum and mitochondrial proteins.J. Amer. Chem. Soc. 87:5570
Hansch, C., Kim, K.H., Sarma, R.H. 1973. Structure-activity relationship in benzamides inhibiting alcohol dehydrogenase.J. Amer. Chem. Soc. 95:6447
Hansch, C., Leo, A., Unger, S.H., Kim, K.H., Nikaitani, D., Lien, E.J. 1973. “Aromatic” substituent constants for structure-activity correlations.J. Med. Chem. 16:1207
Hicklin, J.A. 1959. Salicylate and potassium fluxes of rat diaphragm.Nature 184:2029
Jaffé, H.H. 1953. A re-examination of the Hammett equation.Chem. Rev. 53:191
Lehninger, A.L., Carafoli, E., Rossi, C.S. 1967. Energy-linked ion movements in mitochondrial systems.Adv. Enzymol. 29:259
Leo, A., Hansch, C., Elkins, D. 1971. Partition coefficients and their uses.Chem. Rev. 71:525
Levitan, H., Barker, J.L. 1972a. Salicylate: A structure-activity study of its effects on membrane permeability.Science 176:1423
Levitan, H., Barker, J.L. 1972b. Membrane permeability: Cation selectivity reversibly altered by salicylate.Science 178:63
Levitan, H., Tauc, L., Segundo, J.P. 1970. Electrical transmission among neurons in the buccal ganglion of a mollusc,Navanax inermis.J. Gen. Physiol. 55:484
Machleidt, H., Roth, S., Seeman, P. 1972. The hydrophobic expansion of erythrocyte membranes by the phenol anesthetics.Biochim. Biophys. Acta 255:178
Manchester, K.L., Randle, P.J., Smith, G.H. 1958. Some effects of sodium salicylate on muscle metabolism.Brit. Med. J. 1:1028
McDonald, T.F., Macleod, D.P. 1972. The effect of 2,4-dinitrophenol on electrical and mechanical activity, metabolism and ion movements in guinea-pig ventricular muscle.Brit. J. Pharmacol. 44:711
McLaughlin, S.G.A. 1972. The mechanism of action of DNP on phospholipid bilayer membranes.J. Membrane Biol. 9:361
McLaughlin, S.G.A. 1973. Salicylates and phospholipid bilayer membranes.Nature 243:234
Meech, R.W. 1972. Intracellular calcium injection causes increased potassium conductance inAplysia nerve cells.Comp. Biochem. Physiol. 42 A:493
Meech, R.W. 1974a. Prolonged action potentials inAplysia neurones injected with EGTA.Comp. Biochem. Physiol. 48 A:397
Meech, R.W. 1974b. The sensitivity ofHelix aspersa neurones to injected calcium ions.J. Physiol. (London) 237:259
Mitchell, P. 1966. Chemiosmotic coupling in oxidative and photosynthetic phosphorylation.Biol. Rev. 41:445
Mitchell, P., Moyle, J. 1967. Acid-base titration across the membrane system of rat-liver mitochondria.Biochem. J. 104:588
Mitchell, P., Moyle, J. 1969. Estimation of membrane potential and pH difference across the cristae membrane of rat liver mitochondria.Europ. J. Biochem. 7:471
Omachi, A. 1964. Sulfate transport in human red cells: Inhibition by some uncouplers of oxidative phosphorylation.Science 145:1449
Strickholm, A., Wallin, B.G. 1967. Relative ion permeabilities in the crayfish giant axon determined from rapid external ion changes.J. Gen. Physiol. 50:1929
Vasington, F.D., Murphy, J.V. 1962. Ca++ uptake by rat kidney mitochondria and its dependence on respiration and phosphorylation.J. Biol. Chem. 237:2670
Weast, R.C. (editor). 1971. Handbook of Chemistry and Physics. Chemical Rubber Co., Cleveland, Ohio
Webb, J.L., Hollander, P.B. 1956. Metabolic aspects of the relationship between the contractility and membrane potential of the rat atrium.Circ. Res. 4:618