Inhibition of Mouse and Human Class 1 Aldehyde Dehydrogenase by 4-(N,N-Dialkylamino)Benzaldehyde Compounds

Abstract

The pharmacologic inhibition of the oxidation of aldehydes by aldehyde dehydrogenase (ALDH) has been pursued for over forty years. Disulfiram was first used clinically in an attempt to deter people from ethanol consumption (Hald and Jacobsen, 1948). Disulfiram inhibits the ALDH-catalyzed oxidation of acetaldehyde to acetate, resulting in the accumulation of the more toxic aldehyde metabolite. Unfortunately, disulfiram not only inhibits ALDH enzymes in the liver and erythrocytes, but it also interacts with reactive cysteine thiol side chains of other enzymes. Although identification of the active metabolite responsible for enzyme inhibition in vivo has proven difficult, bioactivation of disulfiram appears to be essential. While strong evidence has been presented that S-methyl N,N-diethylthiocarbamate sulfoxide is the disulfiram metabolite which acts as the in vivo inhibitor of rat liver mitochondrial ALDH (Hart and Faiman, 1992), the sulfone product has also been identified as a potent, irreversible inhibitor and potential in vivo metabolite of disulfiram (Mays et al, 1995).