Allen J W, Shanker G, Aschner M
Department of Physiology and Pharmacology, Wake Forest University, School of Medicine Medical Center Blvd, Winston-Salem, NC 27157-1083, USA.
Brain Res. 2001 Mar 9;894(1):131-40. doi: 10.1016/s0006-8993(01)01988-6.
Maintenance of adequate intracellular glutathione (GSH) levels is vital for intracellular defense against oxidative damage. The toxic effects of methylmercury (MeHg) are attributable, at least in part, to elevated levels of reactive oxygen species, and thus decreases in GSH synthesis may increase methylmercury toxicity. Astrocytes have recently been proposed to play an essential role in providing GSH precursors to neurons. Therefore, cystine transport, a prerequisite to GSH production, was characterized in cultured astrocytes and neurons, and the effects of methylmercury on this transport were assessed. Astrocytes and neurons both possessed temperature dependent transport systems for cystine. Astrocytes accumulated cystine by Na+-independent (X(C)-) and -dependent (X(AG)-) systems while neurons used exclusively Na+-independent systems. Inhibition of the X(AG)- transport system decreased cystine transport in astrocytes to levels equivalent to those in sodium-depleted conditions, suggesting that cystine is carried by a glutamate/aspartate transporter in astrocytes. Inhibition of the multifunction ectoenzyme/amino acid transporter gamma-glutamyltranspeptidase (GGT) decreased cystine transport in both neurons and astrocytes. Inhibition of System X(C)- with quisqualate also decreased cystine uptake in both astrocytes and neurons. These data demonstrate that cultured astrocytes accumulate cystine via three independent mechanisms, System X(AG)-, System X(C)-, and GGT, while cultured hippocampal neurons use System X(C)- and GGT exclusively. Inhibition of cystine uptake in astrocytes by methylmercury appears to be due to actions on the System X(AG)- transporter.
维持足够的细胞内谷胱甘肽（GSH）水平对于细胞内抵御氧化损伤至关重要。甲基汞（MeHg）的毒性作用至少部分归因于活性氧水平的升高，因此GSH合成的减少可能会增加甲基汞的毒性。最近有人提出星形胶质细胞在为神经元提供GSH前体方面发挥着重要作用。因此，在培养的星形胶质细胞和神经元中对胱氨酸转运（GSH产生的先决条件）进行了表征，并评估了甲基汞对这种转运的影响。星形胶质细胞和神经元都具有依赖温度的胱氨酸转运系统。星形胶质细胞通过不依赖钠的（X(C)-）和依赖钠的（X(AG)-）系统积累胱氨酸，而神经元仅使用不依赖钠的系统。抑制X(AG)-转运系统可使星形胶质细胞中的胱氨酸转运降至与钠缺乏条件下相当的水平，这表明胱氨酸在星形胶质细胞中由谷氨酸/天冬氨酸转运体携带。抑制多功能胞外酶/氨基酸转运体γ-谷氨酰转肽酶（GGT）可降低神经元和星形胶质细胞中的胱氨酸转运。用quisqualate抑制系统X(C)-也可降低星形胶质细胞和神经元中的胱氨酸摄取。这些数据表明，培养的星形胶质细胞通过三种独立机制积累胱氨酸，即系统X(AG)-、系统X(C)-和GGT，而培养的海马神经元仅使用系统X(C)-和GGT。甲基汞对星形胶质细胞中胱氨酸摄取的抑制作用似乎是由于对系统X(AG)-转运体的作用。
