PHARMACOLOGY OF DISULFIRAM

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APPLICANT'S ABSTRACT: This is a proposal to continue our studies of the action of disulfiram. Disulfiram is currently the only drug which is approved in the United States for aversion therapy in the treatment of alcoholism. This drug interferes with the metabolism of ethanol by the inhibition of the enzyme aldehyde dehydrogenase (ALDH). The precise mechanism of this effect is related to the formation of one or more active metabolites of disulfiram. The purpose of this study is to examine the pharmacology of disulfiram with respect to the formation of active metabolites, including S-methyl-diethylthiocarbamate sulfoxide, which has been proposed by others as a new therapeutic agent in the treatment of alcoholism. We will examine the inhibition of ALDH by metabolites, as this enzyme is involved in the clinical effect of disulfiram. Mass spectrometry will be used to identify active metabolites as well as to determine how and where inhibitors interact with ALDH. We will also investigate whether free radical formation is involved in the metabolism of disulfiram as this mechanism has implications both for the action as well as for the toxicities of disulfiram. Studies will be performed in vitro, as well as in rats and in humans. We will also use expressed recombinante human ALDH's. The studies described in this proposal will shed new light on the mechanism of action of disulfiram and the pharmacology of its metabolites, more precisely define how aldehyde dehydrogenase is inhibited, and lead to a better understanding of new compounds for the treatment of alcoholism.