Bai Jie, Nakamura Hajime, Kwon Yong-Won, Tanito Masaki, Ueda Shugo, Tanaka Toru, Hattori Itaro, Ban Sadayuki, Momoi Takashi, Kitao Yasuko, Ogawa Satoshi, Yodoi Junji
Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Antioxid Redox Signal. 2007 May;9(5):603-8. doi: 10.1089/ars.2006.1513.
We show that 1-methyl-4-phenylpyridinium ion (MPP(+)), an active metabolite of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), induces cytotoxicity via endoplasmic reticulum (ER)- and mitochondria-mediated pathways, and thioredoxin-1 (TRX-1), a redox-active protein, prevents MPTP-induced neurotoxicity. TRX-1 overexpression suppressed reactive oxygen species and the ATP decline caused by MPP(+) in HepG2 cells. MPP(+) activated caspase-12 in PC12 cells and induced cytotoxicity in HeLa-rho(0) cells lacking mitochondrial DNA, as well as in the parental HeLa-S3 cells. TRX-1-transgenic mice demonstrated significant resistance to caspase-12 activation and the apoptotic decrease of dopaminergic neurons after MPTP administration, compared with wild-type C57BL/6 mice.
我们发现，1-甲基-4-苯基吡啶离子（MPP(+)）是1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的活性代谢产物，它通过内质网（ER）和线粒体介导的途径诱导细胞毒性，而氧化还原活性蛋白硫氧还蛋白-1（TRX-1）可预防MPTP诱导的神经毒性。TRX-1的过表达抑制了HepG2细胞中由MPP(+)引起的活性氧生成和ATP水平下降。MPP(+)在PC12细胞中激活了半胱天冬酶-12，并在缺乏线粒体DNA的HeLa-rho(0)细胞以及亲代HeLa-S3细胞中诱导细胞毒性。与野生型C57BL/6小鼠相比，TRX-1转基因小鼠在给予MPTP后对半胱天冬酶-12的激活和多巴胺能神经元的凋亡减少表现出显著抗性。
