Mkoji G M, Smith J M, Prichard R K
Institute of Parasitology, Macdonald College, McGill University, Ste-Anne de Bellevue, Quebec, Canada.
Biochem Pharmacol. 1989 Dec 1;38(23):4307-13. doi: 10.1016/0006-2952(89)90530-3.
A decrease in reduced glutathione (GSH) levels in adult Schistosoma mansoni exposed in vitro to the antischistosomal drug oltipraz (OPZ) (20-60 nM) was accompanied by a significant increase in oxidized glutathione (GSSG) levels. The total glutathione (GSH + GSSG) levels also diminished in drug-treated parasites. The activities of the parasite glutathione peroxidase (GPO), utilizing cumene hydroperoxide as a substrate, and glutathione S-transferase (GST), measured 18 hr after in vitro incubation with the drug, were elevated significantly, but there were no significant alterations in the activities of the GPO, utilizing H2O2, or glutathione reductase (GR). Drug-treated worms showed increased lipid peroxidation. In vivo, the proportion of the worms recovered from infected mice given OPZ (100 mg/kg body wt) gradually declined with time, to about 30% of that recovered from infected untreated control mice by day 14 after drug administration, and consisted predominantly of male worms. Accompanying this significant decline in the proportion of worms recovered were significant decreases in the activities of the enzymes GR and GST in drug-exposed worms. On the other hand, a slight initial increase in the GPO activity with cumene hydroperoxide was followed by a return to control values, and the GPO activity with H2O2 was decreased only slightly with time. Interestingly, the 4-hydroxyalk-2-enal aldehydes, known products of lipid peroxidation, inhibited the GST reaction with 1-chloro-2,4-dinitrobenzene (CDNB). The OPZ-induced changes in S. mansoni could increase parasite susceptibility to oxidative attack by host phagocytes, and are probably linked with the antischistosomal action of the drug in vivo.
体外暴露于抗血吸虫药物奥替普拉（OPZ，20 - 60 nM）的成年曼氏血吸虫中，还原型谷胱甘肽（GSH）水平降低，同时氧化型谷胱甘肽（GSSG）水平显著升高。药物处理后的寄生虫中总谷胱甘肽（GSH + GSSG）水平也降低。以氢过氧化异丙苯为底物的寄生虫谷胱甘肽过氧化物酶（GPO）和与药物体外孵育18小时后测得的谷胱甘肽S - 转移酶（GST）活性显著升高，但以H2O2为底物的GPO或谷胱甘肽还原酶（GR）活性无显著变化。药物处理的虫体脂质过氧化增加。在体内，给予OPZ（100 mg/kg体重）的感染小鼠体内回收的虫体比例随时间逐渐下降，给药后第14天降至未感染未处理对照小鼠回收虫体比例的约30%，且主要为雄虫。随着回收虫体比例的显著下降，药物暴露虫体中的GR和GST酶活性也显著降低。另一方面，以氢过氧化异丙苯为底物时GPO活性最初略有升高，随后恢复至对照值，以H2O2为底物时GPO活性仅随时间略有下降。有趣的是，脂质过氧化的已知产物4 - 羟基 - 2 - 烯醛抑制了GST与1 - 氯 - 2,4 - 二硝基苯（CDNB）的反应。OPZ诱导的曼氏血吸虫变化可能会增加寄生虫对宿主吞噬细胞氧化攻击的敏感性，并且可能与该药物在体内的抗血吸虫作用有关。
