Brookes N, Kristt D A
Department of Pharmacology, University of Maryland School of Medicine, Baltimore 21201.
J Neurochem. 1989 Oct;53(4):1228-37. doi: 10.1111/j.1471-4159.1989.tb07419.x.
The previously reported observation that submicromolar concentrations of HgCl2 inhibit glutamate uptake reversibly in astrocytes, without effect on 2-deoxyglucose uptake, suggested that elemental mercury vapor, which is oxidized to mercuric mercury in the brain, might cause neurodegenerative change through the mediation of glutamate excitotoxicity. Here, selectivity is explored further by measuring the inhibition of other amino acid transporters and protein synthesis as a function of HgCl2 concentration. The properties of MeHgCl were compared under identical conditions, and some morphological correlates of function were examined. Inhibition of amino acid transport by HgCl2 was selective, whereas MeHgCl was nonselective. The 50% inhibitory concentrations of HgCl2 for uptake of alpha-aminoisobutyric acid by system A, uptake of alpha-aminoisobutyric acid or kynurenine by a system L variant, and uptake of gamma-aminobutyric acid were all two- to fourfold greater than that for uptake of glutamate. The submicromolar concentrations of HgCl2 that inhibited glutamate transport also inhibited protein synthesis, but in a rapidly reversible fashion, and elicited only discrete ultrastructural changes (heterochromatin, increased numbers of lysosomal bodies, and increased complexity of cell surface). In contrast, inhibition of protein synthesis by MeHgCl was acutely (1-h) irreversible and became marked only at concentrations higher than those that elicited gross morphologic change in the form of "bleb"-like swellings. The results lend support to the proposed excitotoxic mediation of mercury vapor neurotoxicity and reveal a sharp contrast between the effects of HgCl2 and MeHgCl on astrocytes.
先前有报道称，亚微摩尔浓度的HgCl₂可在星形胶质细胞中可逆地抑制谷氨酸摄取，而对2-脱氧葡萄糖摄取无影响，这表明在大脑中氧化为汞离子的元素汞蒸气可能通过谷氨酸兴奋性毒性的介导作用导致神经退行性改变。在此，通过测量其他氨基酸转运体的抑制作用以及作为HgCl₂浓度函数的蛋白质合成来进一步探究其选择性。在相同条件下比较了甲基汞氯化物（MeHgCl）的特性，并研究了功能的一些形态学相关性。HgCl₂对氨基酸转运的抑制具有选择性，而MeHgCl则无选择性。HgCl₂对系统A摄取α-氨基异丁酸、系统L变体摄取α-氨基异丁酸或犬尿氨酸以及摄取γ-氨基丁酸的50%抑制浓度均比对谷氨酸摄取的抑制浓度高两到四倍。抑制谷氨酸转运的亚微摩尔浓度的HgCl₂也抑制蛋白质合成，但呈快速可逆方式，且仅引起离散的超微结构变化（异染色质、溶酶体数量增加以及细胞表面复杂性增加）。相比之下，MeHgCl对蛋白质合成的抑制是急性（1小时）不可逆的，且仅在高于引起“泡状”肿胀形式的明显形态学变化的浓度时才变得显著。这些结果支持了所提出的汞蒸气神经毒性的兴奋性毒性介导作用，并揭示了HgCl₂和MeHgCl对星形胶质细胞作用的鲜明对比。
