Inhibition of and interaction with human recombinant mitochondrial aldehyde dehydrogenase by methyl diethylthiocarbamate sulfoxide.

Abstract

Disulfiram is used as aversion therapy in the treatment of alcoholism. Following the administration of disulfiram there is a decrease in the activity of hepatic aldehyde dehydrogenase. A consequence of this effect is the accumulation of acetaldehyde subsequent to ethanol ingestion. The increase in levels of acetaldehyde produce flushing, nausea, vomiting, and tachycardia which is referred to as the disulfiram-ethanol reaction (Hald, et al., 1948; Kitson, 1977). In vivo disulfiram is rapidly reduced to N,N-diethylthiocarbamate (DDC) and it is therefore felt that the intact drug is not responsible for the inhibition of aldehyde dehydrogenase (ALDH) (Cobby, et al., 1977). An active metabolite of disulfiram is felt to be responsible for the inhibition. One such candidate is methyl diethylthiocar-bamate sulfoxide (MeDTC-sulfoxide) (Hart and Faiman, 1992). This compound has been shown to be an inhibitor of rat mitochondrial ALDH and has been detected in the plasma of rats given disulfiram (Hart and Faiman, 1992). Since the mitochondrial isoform of ALDH is felt to be important in the metabolism of acetaldehyde derived from ethanol metabolism (Svanas and Weiner, 1985), we examined the effect of MeDTC-sulfoxide upon the activity of human ALDH. We further investigated the interaction of the inhibitor with this enzyme by mass spectrometry.