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.
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References
Cobby, J., Mayersohn, M. and Selliah, S.: The rapid reduction of disulfiram in blood and plasma. J. Pharmacol. Exp. Ther. 202 (1977) 724–731.
Deitrich, R.A. and Erwin, V.G.: Mechanism of the inhibition of aldehyde dehydrogenase in vivo by disulfiram and diethyldithiocarbamate. Mol.Pharmacol. 7 (1971) 301–307.
Ghenbot, G. and Weiner, H.: Purification of liver aldehyde dehydrogenase by p-hydroxyacetophenone-sepharose affinity matrix and the coelution of chloramphenicol acetyl transferase from the same matrix with recombinantly expressed aldehyde dehydrogenase. Protein.Expr.Purif. 3 (1992) 470–478.
Hald, J., Jacobsen, E. and Larsen, V.: The sensitizing effect of tetraethylthiuramdisulphide (Antabuse) to ethylalcohol. Acta.Pharmacol. 4 (1948) 285–296.
Hart, B.W. and Faiman, M.D.: In vitro and in vivo inhibition of rat liver aldehyde dehydrogenase by S-methyl N,N-diethylthiolcarbamate sulfoxide, a new metabolite of disulfiram. Biochem.Pharmacol. 43 (1992) 403–406.
Jeng, J. and Weiner, H.: Purification and characterization of catalytically active precursor of rat liver mitochondrial aldehyde dehydrogenase expressed in Escherichia coli. Arch.Biochem.Biophys. 289 (1991)–222.
Kitson, T.M.: The disulfiram-ethanol reaction. J. Stud. Alcohol 38 (1977) 96–113.
Mays, D.C., Nelson, A.N., Lam-Holt, J.P., Fauq, A.H. and Lipsky, J.J.: S-Methyl-N,N-diethylthiocarbamate sulfoxide and S-methyl-N-N-diethylthiocarbamate sulfone, two candidates for the active metabolite of disulfiram. Alcohol.Clin.Exp.Res. 20 (1996) 595–600.
Nelson, A.N. and Lipsky, J.J.: Microtiter plate-based determination of multiple concentration-inhibition relationships. Anal.Biochem. 231 (1995) 437–439.
Pietruszko, R., Abriola, D.P., Blatter, E.E. and Mukerjee, N.: Aldehyde dehydrogenase: Aldehyde dehydrogenation and ester hydrolysis. In Weiner, H., Crabb, D.W. and Flynn, T.G. (Eds.), Enzymology and Molecular Biology of Carbonyl Metabolism 4. Plenum Press, New York, NY, 1993, pp. 221–231.
Svanas, G.W. and Weiner, H.: Aldehyde dehydrogenase activity as the rate-limiting factor for acetaldehyde metabolism in rat liver. Arch.Biochem.Biophys. 236 (1985) 36–46.
Zheng, C.-F., Wang, T.T.Y. and Weiner, H.: Cloning and expression of the full-length cDNAs encoding human liver class 1 and class 2 aldehyde dehydrogenase. Alcohol.Clin.Exp.Res. 17 (1993) 828–831.
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© 1996 Springer Science+Business Media New York
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Lipsky, J.J. et al. (1996). Inhibition of and Interaction with Human Recombinant Mitochondrial Aldehyde Dehydrogenase by Methyl Diethylthiocarbamate Sulfoxide. In: Weiner, H., Lindahl, R., Crabb, D.W., Flynn, T.G. (eds) Enzymology and Molecular Biology of Carbonyl Metabolism 6. Advances in Experimental Medicine and Biology, vol 414. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5871-2_24
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DOI: https://doi.org/10.1007/978-1-4615-5871-2_24
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