PHARMACOLOGY OF DISULFIRAM

这是一项研究双硫仑作用机制的建议。 双硫仑是目前唯一在美国获得批准的药物 厌恶疗法在酒精中毒治疗中的地位。尽管它 已知这种药物会抑制乙醛酶 脱氢酶，从而干扰乙醇的新陈代谢， 确切的机制尚不清楚。这项研究的目的是明确 确定二硫兰抑制乙醛脱氢酶的方式 活着。由于双硫仑代谢物的激活似乎是 涉及到抑制，这些研究将集中在这种激活上 途径，特别是甲基化和氧化。研究将会是 在微体系统、动物和人类中执行的。活性代谢物 双硫胺的含量将用质谱仪鉴定。此外，我们 将解决对双硫兰反应不同的问题 这在临床上使用时可以看到。一个可能的解释是 这一发现是二硫胺代谢的遗传差异 可能会导致不同程度的乙醛脱氢酶抑制。我们 将在动物和人类身上测试基因多态 甲基化是造成观察到的变异的原因。这些研究 本建议书中描述的内容将更好地理解 双硫仑的作用机制--临床变异的基础 它的使用，并可能导致开发新的合理战略 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.