title: Triorganotins inhibit the mitochondrial inner membrane anion channel.
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.
authors.affiliation: Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
authors.forename: M F
authors.initials: MF
authors.lastname: Powers
authors.forename: A D
authors.initials: AD
authors.lastname: Beavis
mesh_terms: D002731:4-Chloromercuribenzenesulfonate / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000378:metabolism; D001692:Biological Transport; D002417:Cattle; D002712:Chlorides / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008314:Malonates / Q000378:metabolism; D008628:Mercury / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000494:pharmacology*
chemical_list: D000838:Anions; D002712:Chlorides; D007473:Ion Channels; D008314:Malonates; D013440:Sulfides; D014220:Trialkyltin Compounds; D009569:Nitric Oxide; D014050:Toluene; C011559:tributyltin; D002731:4-Chloromercuribenzenesulfonate; D008628:Mercury; C004848:dithiol; C033479:sodium sulfide