El-Bassiouni E A, Helmy M H, Abdel-Hamid M A, Shohayeb M A, Ismail S S
Department of Pharmacology, Medical Research Institute, Alexandria University, Egypt.
Br J Biomed Sci. 2004;61(1):15-21. doi: 10.1080/09674845.2004.11732640.
The direct effects of oltipraz (OPZ) on mouse hepatocytes and Schistosoma mansoni worms are studied in vitro at a concentration range of 5-25 micromol/L following one- and three-hour incubations. Oxidative stress is reflected by increases in malondialdehyde (MDA), representing the end products of lipid peroxidation, and depletion of glutathione (GSH), representing protective thiol groups. Activities of glutathione peroxidase isoenzymes, GST and GR as components of antioxidative defence are also determined. The opposite effects of low concentrations of OPZ on mammalian hepatocytes and S. mansoni worms were confirmed. In incubation with S. mansoni, addition of OPZ resulted in significantly increased production of MDA, together with depletion of GSH, both of which were time- and OPZ concentration-dependent. In incubation with mouse hepatocytes, however, there was little change in MDA concentrations, and a gradual increase in GSH levels, both of which were time- and concentration-dependent. Addition of OPZ to the incubation media also affected the activities of antioxidant enzymes. Although total GPx activity increased in both mammalian hepatocyte and S. mansoni experiments, the opposite was noted with the selenium-dependent isoenzyme. While there was a gradual increase in sGPx in hepatocytes, there was a time- and concentration-dependent inhibition in the worm isoenzyme. Contrasting results were also obtained with GR. While increased activity was obtained with the enzyme from mouse hepatocytes, the worm enzyme was inhibited, especially at the upper end of the OPZ concentration range and also following longer periods of incubation. The increase in GST activity followed the same qualitative pattern in both hepatocytes and schistosomes. Therefore, OPZ given in doses that maintain a serum concentration in the range 5-25 micromol/L induces biochemical changes in mouse hepatocytes that could be utilised for chemo-preventive purposes and prevention of oxidative damage. However, progressive oxidative damage to S. mansoni worms occurred despite some protective biochemical changes.
在体外研究了奥替普拉（OPZ）在5 - 25微摩尔/升浓度范围内对小鼠肝细胞和曼氏血吸虫的直接作用，孵育时间分别为1小时和3小时。氧化应激通过丙二醛（MDA）增加反映，MDA代表脂质过氧化的终产物，以及谷胱甘肽（GSH）消耗反映，GSH代表保护性硫醇基团。还测定了作为抗氧化防御成分的谷胱甘肽过氧化物酶同工酶、谷胱甘肽S - 转移酶（GST）和谷胱甘肽还原酶（GR）的活性。证实了低浓度OPZ对哺乳动物肝细胞和曼氏血吸虫有相反的作用。与曼氏血吸虫孵育时，添加OPZ导致MDA产生显著增加，同时GSH消耗，两者均呈时间和OPZ浓度依赖性。然而，与小鼠肝细胞孵育时，MDA浓度变化不大，GSH水平逐渐升高，两者均呈时间和浓度依赖性。向孵育培养基中添加OPZ也影响抗氧化酶的活性。虽然在哺乳动物肝细胞和曼氏血吸虫实验中总GPx活性均增加，但硒依赖性同工酶的情况相反。肝细胞中硒依赖性谷胱甘肽过氧化物酶（sGPx）逐渐增加，而蠕虫同工酶则呈时间和浓度依赖性抑制。GR也得到了相反的结果。虽然小鼠肝细胞中的酶活性增加，但蠕虫酶受到抑制，特别是在OPZ浓度范围上限以及孵育较长时间后。GST活性的增加在肝细胞和血吸虫中遵循相同的定性模式。因此，给予维持血清浓度在5 - 25微摩尔/升范围内的OPZ剂量可诱导小鼠肝细胞发生生化变化，可用于化学预防目的和预防氧化损伤。然而，尽管有一些保护性生化变化，曼氏血吸虫仍发生了渐进性氧化损伤。
