Effect of disulfiram (tetraethylthiuram disulfide) on mitochondrial oxidations

Abstract

Disulfiram inhibits the oxidation of NAD-linked substrates by mitochondria but does not affect their succinoxidase activity. The oxidation of β-hydroxybutyrate was totally blocked by 0·27 mM disulfiram. Disulfiram did not change the P/O ratios. Uncoupled mitochondria were less sensitive to disulfiram than phosphorylating mitochondria. Disulfiram inhibited the dinitrophenol-activated ATPase of mitochondria by about 60 per cent whilst having little effect on Mg 2+-activated ATPase. The ATP-P i exchange reaction was approximately 50 per cent inhibited by disulfiram. The inhibitory effect of disulfiram on mitochondria is irreversible. 2-Mercaptoethanol protected the mitochondria if present before the addition of disulfiram. The mechanism of action of disulfiram and the implications of the results for the understanding of the disulfiram-alcohol reaction and the mechanism of oxidative phosphorylation are discussed.