Triorganotins inhibit the mitochondrial inner membrane anion channel.
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.
Powers
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Department of Pharmacology, Medical College of Ohio, Toledo 43699-0008.
Beavis
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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*
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