Mechanism of the Uncoupling Action of Tolbutamide

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Tolbutamide has been reported to be an uncoupler of oxidative phosphorylation of liver mitochondria. However, its mechanism of uncoupling is not fully elucidated. We obtained the following results by measuring oxygen uptake and the swelling of rat liver mitochondria in the presence of tolbutamide and Ca2+. 1) In the presence of O.1 mM EGTA, respiration of liver mitochondria was not influenced by the addition of 1 mM tolbutamide or 0.3 mM Ca2+. However, controlled respiration of mitochondria was released by the concomitant addition of 1 mM tolbutamide and 0.3 mM Ca2+. 2) In the presence of 0.1 mM EGTA, the swelling of liver mitochondria was not influenced by the addition of 2 mM tolbutamide or 0.3 mM Ca2+. However, the concomitant addition of tolbutamide and Ca2+ induced drastic swelling of liver mitochondria. 3) Addition of O.2 mM EGTA caused partial restoration of the uncoupling action of 3.8 mM tolbutamide. Addition of 0.2 mM EGTA and O.4 mM Ca2+ accelerated the uncoupling action of 2.0 mM and 3.8 mM tolbutamide. The above results indicate that tolbutamide changes the ability of the membrane to allow Ca2+, either outside or inside the mitochondria, through the membrane.
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