Chloride‐Hydroxide Exchange across Mitochondrial, Erythrocyte and Artificial Lipid Membranes Mediated by Trialkyl‐ and Triphenyltin Compounds

Abstract

Studies of the effects of trimethyltin, tripropyltin, tributyltin and triphenyltin chlorides on the permeability of the inner mitochondrial membrane by the osmotic swelling technique in NaCl and NH,C1 media show that these compounds mediate transport of chloride ions. Studies in KC1 media show that these compounds mediate a strictly coupled chloride-hydroxide antiporter transport. This exchange allows rapid titration of mitochondrial contents by pulses of HCl. Similar results on erythrocytes and smectic mesophases indicate that this is a direct action of the tin compounds and is not due to modification ofa pre-existing anion carrier in the membrane.The highly toxic trialkyltin compounds have been shown to be potent inhibitors of mitochondrial oxidative phosphorylation by Aldridge and Cremer[1], and Sone and Hagihara [2]. Aldridge et al. [3--51 have shown that these compounds also produce several other effects on mitochondria, for example, uncoupling of oxidative phosphorylation, inhibition of the 2,4 dinitrophenol-stimulated ATPase but stimulat'ion of the ATPase in the absence of 2,4 dinitrophenol, a time-dependent inhibition of 2,4 dinitrophenolstimulated respiration and of state 4 respiration. Unlike inhibitors of oxidative phosphorylation such as oligomycin and aurovertin, the trialkyltin compounds are of known structure and chemical investigation of their mode of action may be possible.A preliminary communication by Selwyn, Stockdale and Dawson [6] outlined investigations intended to define the mode of action of trialkyltin compounds on mitochondria and reported that these compounds produced a rapid chloride-hydroxide exchange across the mitochondrial membrane. This paper describes the effect of trialkyltin compounds on the permeability properties of mitochondrial membranes, erythrocytes and smectic mesophase (liposome) artificial membrane systems.Unusual Abbreviations. Carbonylcyanide p-trifluoromethoxy phenylhydrazone, FCCP ; ethylene glycol-bis-(aminoethy1)-tetraacetic acid, EGTA; N-2-hydroxymethylpiperazine-N'-2-ethanesulphonic acid, HEPES.Enzymes. Carbonic anhydrase or carbonate hydro-lyase (EC 4.2.1.1). MATERIALS AND METHODS MitochondriaMitochondria prepared from the livers of adult (150 to 250 g) Wistar rats were used throughout this investigation. The rats were killed by decapitation and the mitochondria prepared by the method of Hogeboom et al. [7] with the following modifications. The isolation medium was 0.25 M sucrose, deionised by passage through a column of Permutit "Deminrelit" mixed bed resin, and contained 5 mM HEPES adjusted to pH 7.5 with sodium hydroxide. The final centrifugation was performed a t 14 500 x g for 10 min. A light fluffy layer on top of the mitochondrial pellet was poured off with the supernatant fluid and the tightly packed mitochondrial pellet resuspended in the same medium t o give a final concentration of about 80 mg/ml mitochondrial protein. ErythrocytesErythrocytes were prepared from human blood (containing acid-citr ate dextrose anti-coagulant) obtained from the r...

Biological activity of organotin compounds—An overview

“…The effects of the triorganotin compounds on mitochondria have been studied intensively (Aldridge and Cremer, 1955;Aldridge, 1958Aldridge, , 1976Aldridge and Street, 1964;Selwyn et al, 1970;Selwyn, 1976). Three different types of interaction with the mitochondrial respiration could be distinguished.…”

Effects of tri-n-butyltin chloride on energy metabolism, macromolecular synthesis, precursor uptake and cyclic AMP production in isolated rat thymocytes

“…The properties of trialkyltin compounds to interfere with mitochondrial energy production have been intensively studied [6][7][8][9]. Three different mechanisms for disturbing mitochondrial ATP synthesis were distinguished: (i) by mediating the exchange of halide for hydroxyl ions across the mitochondrial membranes; (ii) by binding to a component of the mitochondrial Mg2+-ATPase to produce an oligomycin-like effect; and (iii) by causing gross mitochondrial swelling.…”

Effects of various inhibitors of oxidative phosphorylation on energy metabolism, macromolecular synthesis and cyclic AMP production in isolated rat thymocytes. A regulating role for the cellular energy state in macromolecular synthesis and cyclic AMP production

“…The mechanisms via which the trialkyltin compounds interfere with mitochondrial energy production have been intensively studied [7][8][9]. These compounds inhibit ATP synthesis of isolated rat liver mitochondria by three different mechanisms [9].…”