PHARMACOLOGY OF DISULFIRAM

申请人摘要：这是一项继续研究 双硫仑的作用。 双硫仑是目前唯一一种 在美国获批用于厌恶疗法， 酒精中毒 这种药物干扰乙醇的代谢， 醛脱氢酶（ALDH）的抑制。 的精确 这种效应的机制与一种或多种活性物质的形成有关。 双硫仑的代谢物。 本研究的目的是探讨 双硫仑的药理学， 代谢物，包括S-甲基-二乙基硫代氨基甲酸酯亚砜， 已被其他人提出作为一种新的治疗剂，在治疗 酒精中毒 我们将研究代谢物对ALDH的抑制作用， 酶参与双硫仑的临床作用。 质谱 将用于鉴定活性代谢物以及确定如何和 其中抑制剂与ALDH相互作用。 我们还将调查是否免费 自由基的形成涉及双硫仑的代谢， 作用机制对作用和毒性都有影响 双硫仑 研究将在体外以及大鼠中进行， 在人类身上。 我们还将使用表达的重组人ALDH。 的 本提案中描述的研究将揭示新的机制， 双硫仑的作用及其代谢产物的药理学，更确切地说， 定义醛脱氢酶是如何被抑制的，并导致更好的 了解治疗酒精中毒的新化合物。

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.