This is a proposal to study the mechanism of action of disulfiram. Disulfiram is currently the only drug which is approved in the United States for aversion therapy in the treatment of alcoholism. Although it is known that this drug causes an inhibition of the enzyme aldehyde dehydrogenase, and thus interferes with the metabolism of ethanol, the precise mechanism is unknown. The purpose of this study is to clearly define the manner in which disulfiram inhibits aldehyde dehydrogenase in vivo. Since it appears that activation of metabolites of disulfiram is involved in the inhibition, these studies will focus on such activating pathways, specifically methylation and oxidation. Studies will be performed in microsomal systems, animals, and humans. Active metabolites of disulfiram will be identified by mass spectrometry. In addition, we will address the question of the variation in the response to disulfiram which is seen when it is used clinically. A possible explanation for this finding is that genetic differences in the metabolism of disulfiram may lead to different degrees of aldehyde dehydrogenase inhibition. We will test, in animals as well as in humans whether genetic polymorphisms in methylation are responsible for the observed variations. The studies described in this proposal will provide a better understanding of the mechanism of action of disulfiram, the basis for clinical variation in its use, and may result in a rational strategy for developing new compounds for the treatment of alcoholism.
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