PHARMACOLOGY OF DISULFIRAM

这是一个研究双硫仑作用机制的建议。 双硫仑是目前唯一在美国批准的药物， 厌恶疗法在酒精中毒治疗中的应用。 虽然 已知这种药物会抑制酶醛 脱氢酶，从而干扰乙醇的代谢， 精确的机制是未知的。 本研究的目的是明确 定义双硫仑抑制乙醛脱氢酶的方式， vivo.由于双硫仑代谢物的活化似乎是 参与抑制，这些研究将集中在这种激活 途径，特别是甲基化和氧化。 研究将 在微粒体系统、动物和人类中进行。 活性代谢物 双硫仑将通过质谱法鉴定。 另外我们 将讨论双硫仑反应的变化问题， 这在临床上是可以看到的。 的可能解释 这一发现是双硫仑代谢的遗传差异 可能导致不同程度的醛脱氢酶抑制。 我们 将在动物和人类身上测试基因多态性 甲基化是造成观察到的变异的原因。 研究 本建议书中所述内容将有助于更好地了解 双硫仑的作用机制，临床变异的基础， 它的使用，并可能导致一个合理的战略，开发新的 用于治疗酒精中毒的化合物。

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.