Disulfiram (Antabuse)


Disulfiram (Antabuse) is a drug used in aversion therapy for alcoholism.  The ingestion of antabuse and alcohol results in a very unpleasant physical reaction.   I had a passing acquaintance with Antabuse some thirty years ago and it was not a pleasant experience.  While I knew the mechanism of action was based on inhibition of aldehyde dehydrogenase resulting unpleasant buildup of acetaldehyde (formed by the action of liver alcohol dehydrogenase on ethyl alcohol), I knew little of the chemistry or pharmacology.  As a side note, when I was at the Rockefeller University, I noted that ethyl alcohol was labeled as ethyl hydroxide.  This, as I understand it, was an attempt during prohibition to discourage staff from using the laboratory reagent for non-scientific work. 

This discovery of Antabuse as a drug is an example of serendipity, or more accurately in my opinion, a situation where individuals were clever enough to see everything and not discard an observation because it was not related to the immediate goal AND the interaction of basic science investigators with clinicians (This is called translational medicine today).   It is not unlike the serendipity (or careful examination of data) involved in the discovery of Viagra®(1).

I discussed what I could find at the time on the development of disulfiram in a recent book on the chemical modification of proteins (2).   It turned out that I missed great amount of very interesting history.   Helge Kragh, Professor of History at the University of Aarhus in Denmark published an excellent history of the development  of "antabus" in 2008 (3).  It is interesting to see how some early hints from the rubber industry were missed (or ignored).  It had been observed that workers using disulfiram in the vulcanization of rubber had problems with alcohol consumption (3).  However, there was no apparent recognition of the potential value in the treatment of alcoholism.

Disulfiram was developed as a drug to treat a variety of disorders including intestinal worms.  The two investigators, Drs. Jacobsen and Hald, evaluated the possible side-effects (an early phase I safety study) with themselves as subjects (never pass an IRB today) and noticed that ingestion of alcohol following the drug resulted in significant distress.  The development of the drug to treat alcoholism came from the interaction of Dr. Jacobsen and Dr. Olaf Martensen-Larsen, a clinician who had worked with alcoholics.

Not having seen Professor Kragh's excellent paper when I wrote the book, I traced the history of disulfiram to publications from the Danish group in 1948 (4) who were quite observant on their own work and very knowledgable of the literature.  The paper is well worth reading as it is likely an example of clever research and clinical observation.   The observation was that exposure to alcohol after ingestion of disulfiram caused an uncomfortable physical response.  Subsequent work  by this group (5) showed elevation of acetaldehyde in subject ingesting alcohol after antabuse administration (I would note that observation of the smell of acetaldhyde in the laboratory as reported by Professor Kragh is far more interesting).  Shortly after this work, Eldjarn (6) suggested that diethyldithiocarbamate  was the active species in disulfiram therapy.  While disulfiram can modify purified aldehydrogenase and the chemistry of modification has been described, the in vivo action of disulfiram  appears to be mediated through a metabolite, S-methyl-N,N-diethylthiolcarbamate sulfoxide (7).    It was satisfying to learn the early reactions to alcohol by rubber workers could be explained by that fact that disulfiram (cited as tetraethylthiuram disulfide) and the immediate product of in vivo reduction, diethyldithiocarbamate (as zinc -thiol complex) may act as haptens in the development of allergic responses (8).


References


1.  Campbell, S.F., Science, art and drug discovery: a personal perspective, Clin.Sci. (London) 99, 255-260, 2000.
2.  Lundblad, R.L., Chemical Reagents for Protein Modification, 4th edn., CRC/Taylor and Francis, Boca Raton, Florida, USA, 2014.
3.  Kragh, H., From disulfiram to antabuse: the invention of a drug, Bull.Hist.Chem. 33, 82-88, 2008.
4.  Hald, J., Jacobsen, E., and Larsen, V., The sensitizing effect of tetraethylthiuramdisulphide (Antabuse) to ethylalcohol,  Acta Pharmacol. 4, 285-296, 1948.
5. Hald, J., Jacobsen, E., and Larsen, V., Formation of acetaldehyde in the organism in relation to dosage of antabuse(tetraethylthiuramdisulphide) and to alcohol-concentration in blood,  Acta Pharmacol. 5, 179-188, 1949.
6.   Eldjarn, L., The metabolism of tetraethylthiuramdisulphide (antabuse; aversan) in man, investigated by means of radioactive sulphide, Scand.J.Clin.Lab.Invest. 2, 202-208, 1950.
7.  Hart, B.W. and Faiman, M.D., In vitro and in vivo inhibition of rat liver aldehyde dehydrogenase by S-methyl-N,N-diethylthiolcarbamate, Biochemical Pharmacol. 43, 403-406, 1992.
8.  Chipinda, I., Hettick, J.M., Simoyi, R.H., and Siegel, P.D., Zinc diethyldithiocarbamate allergenicity: potential haptenation mechanism, Contact Dermatitis  59, 79-89, 2008.