Nare B, Smith J M, Prichard R K
Institute of Parasitology, McGill University, Macdonald College, St. Anne de Bellevue, Quebec, Canada.
Biochem Pharmacol. 1991 Aug 22;42(6):1287-92. doi: 10.1016/0006-2952(91)90267-9.
Adult worms of Schistosoma mansoni recovered from mice treated with oltipraz (OPZ) showed a significant diminution in their ability to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) to formazan, a measure of parasite viability. Incubation of glutathione S-transferase (GST) from S. mansoni with OPZ resulted in a time- and concentration-dependent inhibition of enzyme activity. RP 36,642 (an inactive oxy-derivative of OPZ) had a minimal effect on the viability of the worms and no effect on GST activity. The structural integrity of OPZ, particularly the thione sulphur, appears to be necessary for expression of the antischistosomal effects of the drug. OPZ-induced inhibition of GST was non-competitive with either reduced glutathione (GSH) or 1-chloro-2,4-dinitrobenzene (CDNB), indicating that the drug is not a substrate for GST-catalysed conjugation reactions. In addition, the inhibition of GST could not be reversed by dialysis or repurification of the enzyme via a GSH-agarose affinity column. The effects of OPZ on GST activity could render the parasite vulnerable to damage by host-derived reactive oxygen species and aldehydic products of lipid peroxidation. The effects of OPZ on GST activity may play a role in the antischistosomal action of OPZ.
从用奥替普拉（OPZ）治疗的小鼠体内回收的曼氏血吸虫成虫，其将3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四氮唑（MTT）还原为甲臜的能力显著降低，甲臜是衡量寄生虫活力的指标。曼氏血吸虫的谷胱甘肽S-转移酶（GST）与OPZ一起孵育会导致酶活性出现时间和浓度依赖性抑制。RP 36,642（OPZ的一种无活性氧衍生物）对虫体活力影响极小，对GST活性无影响。OPZ的结构完整性，尤其是硫酮硫，似乎是该药物抗血吸虫作用发挥的必要条件。OPZ诱导的GST抑制作用对还原型谷胱甘肽（GSH）或1-氯-2,4-二硝基苯（CDNB）均无竞争性，这表明该药物不是GST催化共轭反应的底物。此外，通过透析或经GSH-琼脂糖亲和柱对酶进行再纯化，均无法逆转GST的抑制作用。OPZ对GST活性的影响可能使寄生虫易受宿主来源的活性氧和脂质过氧化醛类产物的损伤。OPZ对GST活性的影响可能在OPZ的抗血吸虫作用中发挥作用。
