PHARMACOLOGY OF DISULFIRAM

申请者摘要：这是一项继续我们对 双硫仑的作用。双硫兰是目前唯一一种 在美国被批准用于厌恶疗法治疗 酗酒。这种药物通过抑制乙醇的代谢而影响其代谢 乙醛脱氢酶(ALDH)的抑制。精准的 其作用机制与一种或多种活性物质的形成有关。 双硫仑的代谢物。这项研究的目的是考察 双硫仑对活性物质形成的药理作用 代谢物，包括S-甲基二乙基硫代氨基甲酸亚砜，它有 被其他人提议作为一种新的治疗剂用于治疗 酗酒。我们将检查代谢物对ALDH的抑制，因为 酶参与了双硫仑的临床疗效。质谱学 将被用来识别活性代谢物以及确定如何和 抑制剂与ALDH相互作用的地方。我们还将调查是否免费 自由基的形成参与了双硫兰的代谢，因为 机制对作用和毒性都有影响。 双硫仑。研究将在体外进行，以及在大鼠和 在人类身上。我们还将使用表达的重组人ALDH。 这项提案中描述的研究将为揭示 更准确地说，双硫仑的作用及其代谢物的药理学 定义乙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.