Chinta Shankar J, Kumar Jyothi M, Zhang Hongqiao, Forman Henry Jay, Andersen Julie K
Buck Institute for Age Research, Novato, CA 94945, USA.
Free Radic Biol Med. 2006 May 1;40(9):1557-63. doi: 10.1016/j.freeradbiomed.2005.12.023. Epub 2006 Jan 13.
Up-regulation of activity of gamma-glutamyl transpeptidase (GGT) has been reported to occur in the Parkinsonian substantia nigra, the area of the brain affected by the disease. Increased GGT activity has been hypothesized to play a role in subsequent mitochondrial complex I (CI) inhibition by increasing cysteine as substrate for cellular uptake. Intracellular cysteine has been proposed to form toxic adducts with dopamine which can be metabolized to compounds which inhibit CI activity. We have demonstrated that in addition to CI inhibition, GGT activity is up-regulated in dopaminergic cells as a consequence of glutathione depletion. Inhibition of GGT rather than resulting in increased CI inhibition results in exacerbation of this inhibitory effect. This suggests that increased GGT activity is likely an adaptive response to the loss of glutathione to conserve intracellular glutathione content and results in a compensatory effect on CI activity rather than in its inhibition as has been previously widely hypothesized.
据报道，在帕金森病患者受影响的脑区——黑质中，γ-谷氨酰转肽酶（GGT）的活性会上调。有人推测，GGT活性增加通过增加半胱氨酸作为细胞摄取的底物，在随后的线粒体复合物I（CI）抑制中发挥作用。有人提出，细胞内的半胱氨酸会与多巴胺形成有毒加合物，这些加合物可代谢为抑制CI活性的化合物。我们已经证明，除了CI抑制外，由于谷胱甘肽耗竭，多巴胺能细胞中的GGT活性也会上调。抑制GGT非但不会导致CI抑制增加，反而会加剧这种抑制作用。这表明，GGT活性增加可能是对谷胱甘肽丧失的一种适应性反应，以保存细胞内谷胱甘肽含量，并对CI活性产生补偿作用，而不是像之前广泛假设的那样导致其抑制。
