Triorganotins inhibit the mitochondrial inner membrane anion channel.

Published on Sep 15, 1991in Journal of Biological Chemistry 4.01
M F Powers4
Estimated H-index: 4
Andrew D. Beavis13
Estimated H-index: 13
Abstract The inner membrane of liver and heart mitochondria possesses an anion uniport pathway, known as the inner membrane anion channel (IMAC). IMAC is inhibited by matrix Mg2+, matrix H+, N,N'-dicyclohexycarbodiimide, mercurials and amphiphilic amines such as propranolol. Most of these agents react with a number of different mitochondrial proteins and, therefore, more selective inhibitors have been sought. In this paper, we report the discovery of a new class of inhibitors, triorganotin compounds, which block IMAC completely. One of the most potent, tributyltin (TBT) inhibits malonate uniport via IMAC 95% at 0.9 nmol/mg. The only other mitochondrial protein reported to react with triorganotins, the F1F0ATPase, is inhibited by about 0.75 nmol/mg. The potency of inhibition of IMAC increases with hydrophobicity in the sequence trimethyltin much less than triethyltin much less than tripropyltin less than triphenyltin less than tributyltin; which suggests that the binding site is accessible from the lipid bilayer. It has long been established that triorganotins are anionophores able to catalyze Cl-/OH- exchange; however, TBT is able to inhibit Cl- and NO3- transport via IMAC at doses below those required to catalyze rapid rates of Cl-/OH- exchange. Consistent with previous reports, the data indicate that about 0.8 nmol of TBT per mg of mitochondrial protein is tightly bound and not available to mediate Cl-/OH- exchange. We have also shown that the mercurials, p-chloromercuribenzene sulfonate and mersalyl, which only partially inhibit Cl- and NO3- transport can increase the IC50 for TBT 10-fold. This effect appears to result from a reaction at a previously unidentified mercurial reactive site. The inhibitory dose is also increased by raising the pH and inhibition by TBT can be reversed by S2- and dithiols but not by monothiols.
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Cited By63
Published on Mar 1, 2009in FEBS Journal 4.53
Kathleen Kupsch4
Estimated H-index: 4
(Otto-von-Guericke University Magdeburg),
Silvia Hertel4
Estimated H-index: 4
(Otto-von-Guericke University Magdeburg)
+ 4 AuthorsPeter Schönfeld27
Estimated H-index: 27
(Otto-von-Guericke University Magdeburg)
There is an ongoing debate on the presence of beneficial effects of minocycline (MC), a tetracycline-like antibiotic, on the preservation of mitochondrial functions under conditions promoting mitochondria-mediated apoptosis. Here, we present a multiparameter study on the effects of MC on isolated rat liver mitochondria (RLM) suspended either in a KCl-based or in a sucrose-based medium. We found that the incubation medium used strongly affects the response of RLM to MC. In KCl-based medium, but n...
28 Citations Source Cite
Published on Jun 1, 2008in Toxicology in Vitro 3.10
Alessandra Pagliarani17
Estimated H-index: 17
(University of Bologna),
Patrizia Bandiera4
Estimated H-index: 4
(University of Bologna)
+ 4 AuthorsAnna Rosa Borgatti14
Estimated H-index: 14
(University of Bologna)
Abstract Tributyltin (TBT), one of the most toxic lipophilic aquatic pollutants, can be efficiently incorporated from sea water and sediments by filter-feeding molluscs. As far as we are aware TBT effects on the mitochondrial oligomycin-sensitive Mg-ATPase, the enzymatic core of energy production and a known target of TBT toxicity in mammals, have not been yet investigated in molluscs; thus the hydrolytic capability of the mitochondrial complex in the presence of micromolar concentrations of TBT...
20 Citations Source Cite
Published on Jun 11, 1993in Toxicology 3.27
S. Reader1
Estimated H-index: 1
(Université du Québec à Montréal),
Michel Marion16
Estimated H-index: 16
(Université du Québec à Montréal),
Francine Denizeau22
Estimated H-index: 22
(Université du Québec à Montréal)
Abstract The toxic effects of tri- n -butylin chloride (TBT) were investigated on isolated trout hepatocytes by flow cytometry (FCM). We developed a procedure permitting the study of cytosolic free calcium in these cells using the new fluorescent probe Fura Red. In parallel, changes in thiol levels upon exposure to TBT were also followed by FCM with the probe 5-chloromethylfluorescein-diacetate. Cell viability was monitored through FCM analysis using propidium iodide. Treatment of hepatocytes wi...
43 Citations Source Cite
Published on May 17, 2010in FEBS Letters 3.00
Zuzana Tomaskova7
Estimated H-index: 7
(Slovak Academy of Sciences),
Karol Ondrias23
Estimated H-index: 23
(Slovak Academy of Sciences)
This minireview focuses on observation of the properties, functional significance, and modulation of single chloride channels in the mitochondrial inner membrane using two electrophysiological methods – the patch-clamp and bilayer lipid membrane methods. Measurements of parameters such as conductance, Cl−/K+ selectivity, voltage or pH dependence as well as their modulation by endogenous and exogenous compounds using individual mitochondrial chloride channels result in an unexpectedly wide range ...
25 Citations Source Cite
Published on Feb 1, 1992in Journal of Bioenergetics and Biomembranes 2.91
Andrew D. Beavis13
Estimated H-index: 13
(University of Toledo Medical Center)
The mitochondrial inner membrane possesses an anion channel (IMAC) which mediates the electrophoretic transport of a wide variety of anions and is believed to be an important component of the volume homeostatic mechanism. IMAC is regulated by matrix Mg2+ (IC50=38 µM at pH 7.4) and by matrix H+ (pIC50=7.7). Moreover, inhibition by Mg2+ is pH-dependent. IMAC is also reversibly inhibited by many cationic amphiphilic drugs, including propranolol, and irreversibly inhibited byN,N′-dicyclohexylcarbodi...
116 Citations Source Cite
Published on May 1, 2004in Glia 5.85
Thomas Stahnke4
Estimated H-index: 4
(University of Oldenburg),
Christiane Richter-Landsberg36
Estimated H-index: 36
(University of Oldenburg)
Triethyltin (TET)-induced neurotoxicity in the brain causes the formation of myelin edema and loss. Myelin deficits produced by early postnatal exposure to TET are permanent and cannot be repaired as the brain matures. The underlying causes have not been resolved. To investigate whether TET directly affects oligodendrocytes, the myelin-forming cells of the central nervous system, cultured rat brain oligodendrocytes were prepared and treated with TET. The data show that TET was cytotoxic for olig...
15 Citations Source Cite
Published on Feb 1, 2000in Toxicology and Applied Pharmacology 3.62
Sergi Gassó4
Estimated H-index: 4
(Spanish National Research Council),
Coral Sanfeliu29
Estimated H-index: 29
(Spanish National Research Council)
+ 2 AuthorsRosa Cristòfol20
Estimated H-index: 20
(Spanish National Research Council)
Abstract The environmental contaminants trimethyltin (TMT) and triethyltin (TET) stimulated the spontaneous release of [ 3 H]noradrenaline ([ 3 H]NA) from hippocampal slices in a time- and concentration-dependent manner. TMT was the most potent compound, exhibiting an EC50 value 10-fold lower (3.8 μM) than that of TET (39.5 μM). Metal-evoked [ 3 H]NA release did not increase in the absence of desipramine and was completely blocked by reserpine preincubation, indicating a vesicular origin of [ 3 ...
13 Citations Source Cite
Published on Aug 1, 1998in Journal of Neuroimmunology 2.65
Payal S Mehta1
Estimated H-index: 1
(University of North Carolina at Chapel Hill),
Alessandra Bruccoleri9
Estimated H-index: 9
(National Institutes of Health)
+ 1 AuthorsG. Jean Harry24
Estimated H-index: 24
(National Institutes of Health)
Abstract This study examined the early response of pro-inflammatory and regulatory cytokines in the mouse brain following triethyltin (TET)-induced myelin injury characterized by edematous vacuolation. Following an acute intraperitoneal injection of triethyltin (TET) sulfate (3 mg/kg) to 17-day old CD1 mice, significant increases in brain stem TNF- α and IL-1 α mRNA levels occurred at 6 and 24 h, respectively with elevations in TGF- β 1 and MIP-1 α at 1 h. In the cortex, responses were limited t...
7 Citations Source Cite
Published on Dec 1, 2013in FEBS Journal 4.53
Peter Schönfeld27
Estimated H-index: 27
(Otto-von-Guericke University Magdeburg),
Detlef Siemen22
Estimated H-index: 22
(Otto-von-Guericke University Magdeburg)
+ 2 AuthorsClaudia Franz2
Estimated H-index: 2
(Otto-von-Guericke University Magdeburg)
Several studies have proposed that the antibiotic minocycline (MC) has cytoprotective activities. Nevertheless, when cells have been exposed to MC at micromolar concentrations, detrimental effects have been also observed. Despite the known inhibitory activity of MC on ATP synthesis and the Ca2+ retention capacity of isolated rat liver and brain mitochondria, the underlying mechanism is still debated. Here, we present further arguments supporting our concept that MC acting on rat liver mitochondr...
11 Citations Source Cite
Published on Apr 1, 2006in Marine Biology 2.21
Alice Barbaglio9
Estimated H-index: 9
(University of Milan),
Daniela Mozzi6
Estimated H-index: 6
(University of Milan)
+ 5 AuthorsM. Daniela Candia Carnevali14
Estimated H-index: 14
(University of Milan)
Regenerative phenomena reproduce developmental processes in adult organisms and are regulated by neuro-endocrine mechanisms. They can therefore provide sensitive tests for monitoring the effects of exposure to endocrine disrupter contaminants (EDs) which can be bioaccumulated by the organisms causing dysfunctions in steroid hormone metabolism and activities and affecting reproduction and development. Echinoderms are prime candidates for this new ecotoxicological approach, since (1) they offer un...
16 Citations Source Cite