The effect of triethyltin on mitochondrial swelling.

Triethyltin induces swelling of isolated rat liver mitochondria suspended in sucrose or KC1 media. This effect is not seen with brain mitochondria. Triethyltin swelling is only minimally reduced by EDTA or amytal but is prevented by 2 :Cdinitrophenol, cyanide or salicylate. The addition of adenosine trior diphosphate causes reversal of the swelling; this effect is potentiated by Mn2+ but not by Mg*+. The reversal of thyroxine-induced swelling by ATP is blocked by triethyltin, perhaps via an inhibition of the hydrolysis of adenosine triphosphate. The relationship between in vitro effects of triethyltin on mitochondria and the toxic actions of the drug in the whole animal are discussed. TN ‘rrnz past few years many investigators have studied the phenomenon of mitochondrial swelling.l-s Much of the interest has centered around the role of phosphate bond energy and oxidative phosphorylation in the maintenance of mitochondrial integrity. Substrates, cofactors, ions and more recently agents which uncouple oxidative phosphorylat~on have been examined for their effects upon mitochondrial swelling. Generally, there has been no correlation between uncoupling action and mitochondrial permeability; some uncoupling agents enhance while others protect against mitochondrial swelling.2p 3 The present work will demonstrate the effects of an organo-tin compound on mitochondrial permeability. This compound, triethyltin (TET) is an extremely toxic agent,ss lo a potent uncoupler of oxidative phosphorylationll and an inhibitor of mitochondrial adenosine triphosphatases (ATBases). I2 These studies were initiated with the view that such experiments might yield information pertinent to the elucidation of the phenomenon of mitochondrial swelling and further shed some light upon the mechanism of toxicity of the organo-tin compounds. METHODS ~ito~hondria were isolated from the livers of unstarved Holtzman female rats weighing 200-250 g by the method of Hogeboom et al.ls Brain mitochondria were prepared as described by Brody and Bain. l4 The homogenization fluid was O-25 M sucrose in those experiments in which swelling was determined in KCl-tris (hydroxymethyl) aminomethane (Tris) medium. When swelling was measured in sucrose-Tris medium, O-3 M sucrose and 0.02 M Tris buffer pH 7.4 was used for the preparation and resuspension of the mitochondria. The mitochondria were prepared so that 1-O ml of the final suspension contained the mitochondria from 0.5 g of liver. This stock suspension was kept at O-2 “C and used within 2-3 hr after preparation. Swelling experi* Preliminary studies were reported in Fed. Prac. 19, 139 (1960). t Present address: Department of Pharmacology, Dartmouth Medical School, Hanover, NH.