ROLE OF GLUTATHIONE IN DRUG METABOLISM BY SCHISTOSOMES

据估计，血吸虫病折磨着2亿多人。 国际吧 在研制出实用的疫苗之前， 对于治疗受感染的个体和 控制人群内传播的计划。 显著 向合理发展的新的，更有效的 详细了解以下内容将有助于抗β-内酰胺酶药物 药物-寄生虫相互作用的生化机制。 等 相互作用不仅包括药物对寄生虫的影响， 以及寄生虫对药物的影响。 因此， 酶体对异生物质化合物的酶促解毒能力 可以解释一些观察到的菌株或种属差异， 易感性 这一提议旨在检验以下假设： 还原型谷胱甘肽（GSH）是一种外源性代谢途径， 可能参与某些药物的解毒作用 寄生虫 研究将集中在谷胱甘肽S-转移酶 (GST)以及它们在催化这种缀合反应中的作用。 的 还将考虑推定的GSH缀合物的后续命运。 具体的实验目的如下：1）利用现有的检测方法 对于GST，调查无细胞催化的GSH依赖性反应的类型 曼氏血吸虫成虫GST的纯化;曼索尼比 亲和层析和高压液相层析; 在理化性质方面表征纯化的酶/同工酶 性质和催化和配体结合功能， 生物化学技术; 3）使用模型底物和特异性抗血清， 记录S. mansoni在发展过程中 从尾蚴到成虫; 4）同样，探索是否有染色体GST 5）比较S. mansoni和S.以确定是否存在物种差异， 代谢敌敌畏的能力，敌百虫的活性形式， 说明不同物种对该药物的敏感性;以及6） 用放射性标记的模型药物和高压液相色谱 分析，确定是否成年S.曼氏排谷胱硫醚 直接结合或是否进一步代谢为其他药物 产品如巯基尿酸。

Schistosomiasis is estimated to afflict well over 200 million people worldwide. Until a practical vaccine is available, chemotherapy will continue to be important both for treating infected individuals and in programs for controlling transmission within populations. Significant advances toward the rational development of new, more effective antischistosomal drugs will be facilitated by a detailed understanding of the biochemical mechanisms underlying drug-parasite interactions. Such interactions include not only the effects of a drug on the parasite, but also effects of the parasite on the drug. Thus, differences in the capacity of schistosomes to enzymatically detoxicate xenobiotic compounds could explain some observed strain or species differences in drug susceptibility. This proposal is designed to test the hypothesis that conjugation with reduced glutathione (GSH) is a pathway of xenobiotic metabolism in schistosmes and may be involved in the detoxication of some drugs by these parasites. Studies will focus on schistosomal glutathione S-transferases (GST) and their role in catalyzing such conjugation reactions. The subsequent fate of putative GSH conjugates will also be considered. Specific experimental objectives are as follows: 1) Using existing assays for GST, survey the types of GSH-dependent reactions catalyzed by cell-free Schistosoma mansoni preparations; 2) Purify GST from adult S. mansoni by affinity chromatography and high pressure liquid chromatography; characterize the purified enzyme/isoenzymes with respect to physicochemical properties and catalytic and ligand binding functions using standard biochemical techniques; 3) With model substrates and specific antisera, document changes in the expression of GST in S. mansoni during development from cercaria to adult; 4) Similarly, explore whether schistosomal GST is inducible by treatment with certain xenobiotics; 5) compare GST in S. mansoni and S. hematobium to determine whether species differences in the capacity to metabolize dichlorvos, the active form of metrifonate, can account for the differential species susceptibility to that drug; and 6) With a radiolabeled model drug and high pressure liquid chromatograhic analysis, determine whether adult S. mansoni excrete GSH thioether conjugates directly or whether these are further metabolized to other drug products such as mercapturic acids.