Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Sillim-dong, Gwanak-gu, Seoul 151-742, Korea, Republic of Korea.
Expert Opin Drug Metab Toxicol. 2010 Feb;6(2):213-24. doi: 10.1517/17425250903427972.
Comprehensive studies indicate that oltipraz exerts cancer chemopreventive effects. Oltipraz has other therapeutic potentials, which include anti-fibrotic effect, inhibition of insulin resistance, mitochondrial protection and cytoprotective effect against oxidative stress. Although antioxidant mechanisms may account for its cancer chemopreventive effect, details on the molecular mechanism still remain to be clarified.
Two major metabolic pathways of oltipraz include oxidative desulfuration of the thione to yield 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one and molecular rearrangement to 7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine. In addition to the diverse pharmacological effects of oltipraz, the oxidized metabolites may have distinct biological effects on cell survival. The AMP-activated protein kinase pathway has been recognized as a key cascade for mitochondrial protection and cell survival events, which can be activated by the oxidized metabolites of oltipraz.
In this review, the metabolic activation of oltipraz and the role of the cell signaling pathways in regulating the expression of Phase II genes and antioxidant activity are discussed with particular reference to their effects on mitochondrial protection and cell survival.
In terms of therapeutic potential, the findings reviewed here demonstrate a therapeutic potential for oxidized metabolite of oltipraz and offer comparison of antioxidant capacity between metabolites and parent compound.
综合研究表明，奥替普拉具有抗癌化学预防作用。奥替普拉还具有其他治疗潜力，包括抗纤维化作用、抑制胰岛素抵抗、线粒体保护和对氧化应激的细胞保护作用。尽管抗氧化机制可能解释了其抗癌化学预防作用，但分子机制的细节仍有待阐明。
奥替普拉的两种主要代谢途径包括将硫酮氧化脱硫生成 4-甲基-5-(吡嗪-2-基)-3H-1,2-二硫-3-酮和分子重排生成 7-甲基-6,8-双(甲硫基)H-吡咯并[1,2-a]吡嗪。除了奥替普拉的多种药理学作用外，氧化代谢物可能对细胞存活具有不同的生物学作用。AMP 激活的蛋白激酶途径已被认为是线粒体保护和细胞存活事件的关键级联反应，奥替普拉的氧化代谢物可以激活该途径。
在这篇综述中，讨论了奥替普拉的代谢激活以及细胞信号通路在调节 II 相基因表达和抗氧化活性中的作用，特别提到了它们对线粒体保护和细胞存活的影响。
就治疗潜力而言，这里综述的研究结果表明奥替普拉氧化代谢物具有治疗潜力，并比较了代谢物和母体化合物的抗氧化能力。
