Inhibition of Mouse and Human Class 1 Aldehyde Dehydrogenase by 4-(N,N-Dialkylamino)Benzaldehyde Compounds
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).
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- Kohn, F.R., Landkamer, G.J., Manthey, C.L., Ramsay, N.K., and Sladek, N.E. Effect of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and malignant blood cells to oxazaphosphorines. Cancer. Res. 47:3180–3185, 1987.PubMedGoogle Scholar
- Maki, P.A. and Sladek, N.E. Sensitivity of aldehyde dehydrogenases in murine tumor and hematopoietic progenitor cells to inhibition by chloral hydrate as determined by the ability of chloral hydrate to potentiate the cytotoxic action of mafosfamide. Biochem. Pharmacol. 45:231–239, 1993.PubMedCrossRefGoogle Scholar
- Mays, D.C., Nelson, A.N., Fauq, A.H., Shriver, Z.H., Veverka, K.A., Naylor, S., and Lipsky, J.J. S-Methyl N,N-Diethylthiocarbamate Sulfone, A potential Metabolite of Disulfiram and Potent Inhibitor of Low Km Mitochondrial Aldehyde Dehydrogenase. Biochem. Pharmacol. 49: 693–700, 1995.PubMedCrossRefGoogle Scholar
- Poole, R.C., Bowden, N.J., and Halestrap, A.P. Derivatives of cinnamic acid interact with the nucleotide binding site of mitochondrial aldehyde dehydrogenase. Biochem. Pharmacol. 45: 1621–1630, 1993.Google Scholar
- Russo, J.E., Hilton, J., and Colvin, O.M. The Role of Aldehyde Dehydrogenase Isozymes in Cellular Resistance to the Alkylating Agent Cyclophosphamide. In: Enzymology and Molecular Biology of Carbonyl Metabolism 2. Flynn, T.G. and Weiner, H.,) pp. 65–79. Alan R. Liss, New York 1989.Google Scholar
- Sladek, N.E., Sreerama, L., and Rekha, G.K. Constitutive and Overexpressed Human Cytosolic Class-3 Aldehyde Dehydrogenases in Normal and Neoplastic Cells/Secretions. In Enzymology and Molecular Biology of Carbonyl Metabolism 5; Weiner, H., Holmes, R.S., and Wermuth, B., eds. Plenum Press, N.Y. pp. 103–113, 1995.CrossRefGoogle Scholar