Aschner M, Conklin D R, Yao C P, Allen J W, Tan K H
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Brain Res. 1998 Dec 7;813(2):254-61. doi: 10.1016/s0006-8993(98)00947-0.
Metallothionein (MT) proteins play an important role in the detoxification of heavy metals. Since methylmercury (MeHg) preferentially accumulates in astrocytes, we investigated the ability of the astrocyte-specific MT isoform, MT-I, to attenuate MeHg-induced cytotoxicity. Increased astrocytic MT expression was achieved by 24-h pretreatment of neonatal rat primary astrocyte cultures with 100 microM zinc (ZnSO4). Subsequently, the astrocytes were treated with MeHg (10 microM), and its toxic effects on cell volume, Na+ uptake, and K+ release were investigated and compared to cells treated with or without MeHg, but in the absence of Zn pretreatment. Pretreatment of astrocytes with Zn was associated with a 2.9-fold increase in MT protein levels (P<0.02), and a 5.6-fold increase in MT mRNA levels (p<0.002) compared to control astrocytes. Astrocytes expressing increased MT protein levels were resistant to MeHg-induced swelling. In isotonic buffer the effect of MeHg on swelling was abolished (p<0.01) by 24-h Zn pretreatment, in such a way that volume profiles in these cells did not differ from controls. Zn-induced increased expression of MTs was also associated with significant attenuation of astrocytic Na+ uptake (p<0.01) and Rb+ (a marker for K+) release (p<0.001) in response to treatment with MeHg. These results demonstrate (1) that astrocytes can be induced to express high levels of MT proteins by pretreatment with Zn, and (2) that Zn confers resistance against the acute effect of MeHg on astrocytic swelling and the associated changes in ion (Na+ and K+) transport. Taken together, the data suggest that astrocytic MT induction offers effective cellular adaptation to MeHg cytotoxicity.
金属硫蛋白（MT）在重金属解毒过程中发挥着重要作用。由于甲基汞（MeHg）优先蓄积于星形胶质细胞中，我们研究了星形胶质细胞特异性MT亚型MT-I减轻MeHg诱导的细胞毒性的能力。通过用100微摩尔锌（硫酸锌）对新生大鼠原代星形胶质细胞培养物进行24小时预处理，实现了星形胶质细胞MT表达的增加。随后，用MeHg（10微摩尔）处理星形胶质细胞，并研究其对细胞体积、钠摄取和钾释放的毒性作用，并与未用锌预处理但用或未用MeHg处理的细胞进行比较。与对照星形胶质细胞相比，用锌预处理星形胶质细胞与MT蛋白水平增加2.9倍（P<0.02）和MT mRNA水平增加5.6倍（p<0.002）相关。表达增加的MT蛋白水平的星形胶质细胞对MeHg诱导的肿胀具有抗性。在等渗缓冲液中，24小时锌预处理消除了MeHg对肿胀的影响（p<0.01），使得这些细胞的体积变化与对照无差异。锌诱导的MTs表达增加还与星形胶质细胞对MeHg处理的钠摄取（p<0.01）和Rb+（钾的标志物）释放（p<0.001）的显著减轻相关。这些结果表明：（1）通过锌预处理可诱导星形胶质细胞表达高水平的MT蛋白；（2）锌赋予对MeHg对星形胶质细胞肿胀及相关离子（钠和钾）转运变化的急性效应的抗性。综上所述，数据表明星形胶质细胞MT诱导为MeHg细胞毒性提供了有效的细胞适应性。
