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Triorganotins inhibit the mitochondrial inner membrane anion channel.

Published on Sep 15, 1991in Journal of Biological Chemistry
M F Powers5
Estimated H-index: 5
,
Andrew D. Beavis13
Estimated H-index: 13
Abstract
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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Published on Jun 10, 2019in Toxicologic Pathology 1.38
William M. Valentine24
Estimated H-index: 24
Toxic peripheral neuropathies are an important form of acquired polyneuropathy produced by a variety of xenobiotics and different exposure scenarios. Delineating the mechanisms of neurotoxicants an...
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Published on Oct 10, 2018
Katarina Mackova , Anton Misak5
Estimated H-index: 5
,
Zuzana Tomaskova7
Estimated H-index: 7
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Saqib Ali29
Estimated H-index: 29
(QAU: Quaid-i-Azam University),
Saira Shahzadi16
Estimated H-index: 16
(QAU: Quaid-i-Azam University),
Imtiaz-ud-Din10
Estimated H-index: 10
(QAU: Quaid-i-Azam University)
The excellent anticarcinogenicity and toxicity of organotin(IV) complexes of certain acrylates, methylenedioxyphenylpropenoic acid, piperonylic acid, phenylethanoates, carboxylic acid, acetic acid, benzohydroxamato, peptides, dipeptides, benzoates, schiff bases, xylene, nicotinic acid, pyrimidine, and aminoalcohols have been reviewed here. The high cytotoxic activity of complexes is affected by (1) the availability of coordination positions at Sn and (2) the occurrence of relatively stable ligan...
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Published on Mar 16, 2018in Frontiers in Endocrinology 3.63
Vinicius Bermond Marques4
Estimated H-index: 4
,
Rodrigo Alves Faria1
Estimated H-index: 1
,
Leonardo dos Santos14
Estimated H-index: 14
1 Citations Source Cite
Published on Jan 1, 2018
Candice Brinkmeyer-Langford11
Estimated H-index: 11
,
J. Li + 1 AuthorsE. Tiffany-Castiglioni
A compound may be neurotoxic by perturbing a metabolic, structural, or functional property characteristic of myelin or myelinating cells. Perturbations of these properties during nervous system development are more deleterious than those occurring after maturation of the nervous system. Myelin and myelination are described in this section, with emphasis on points relevant to neurotoxic mechanisms of chemicals that target myelin. More information is readily available in more specialized reviews o...
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Published on Jan 1, 2016in Handbook of experimental pharmacology
Devasena Ponnalagu4
Estimated H-index: 4
(Drexel University),
Harpreet Singh14
Estimated H-index: 14
(Drexel University)
Mitochondria are the “power house” of a cell continuously generating ATP to ensure its proper functioning. The constant production of ATP via oxidative phosphorylation demands a large electrochemical force that drives protons across the highly selective and low-permeable mitochondrial inner membrane. Besides the conventional role of generating ATP, mitochondria also play an active role in calcium signaling, generation of reactive oxygen species (ROS), stress responses, and regulation of cell-dea...
8 Citations Source Cite
Published on Nov 1, 2014in Inorganica Chimica Acta 2.43
Sartaj Tabassum25
Estimated H-index: 25
(AMU: Aligarh Muslim University),
Shipra Yadav7
Estimated H-index: 7
(AMU: Aligarh Muslim University),
Farukh Arjmand28
Estimated H-index: 28
(AMU: Aligarh Muslim University)
Abstract The design of metal-based chemotherapeutic drugs depends on choice of ligand framework, therefore, metals incorporated in a bioactive ligand scaffold hold promise for the improved pharmacokinetic profile and better efficacy of drugs. In this context, glycosylated-organotin(IV) antitumor agents are attractive and prove the state-of-the-art design for chemotherapy due to organotin-induced cytotoxicity. In recent years, many organotin(IV) complexes with glycosylated appendage have been dev...
6 Citations Source Cite
Published on Apr 1, 2014in Physiological Reviews 24.25
Ildikò Szabò47
Estimated H-index: 47
(UNIPD: University of Padua),
Mario Zoratti46
Estimated H-index: 46
(UNIPD: University of Padua)
The field of mitochondrial ion channels has recently seen substantial progress, including the molecular identification of some of the channels. An integrative approach using genetics, electrophysiology, pharmacology, and cell biology to clarify the roles of these channels has thus become possible. It is by now clear that many of these channels are important for energy supply by the mitochondria and have a major impact on the fate of the entire cell as well. The purpose of this review is to provi...
123 Citations Source Cite
Published on Dec 1, 2013in FEBS Journal 4.74
Peter Schönfeld27
Estimated H-index: 27
(Otto-von-Guericke University Magdeburg),
Detlef Siemen22
Estimated H-index: 22
(Otto-von-Guericke University Magdeburg)
+ 2 AuthorsL. Wojtzcak40
Estimated H-index: 40
(Nencki Institute of Experimental Biology)
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