Ballatori Nazzareno
Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.
Environ Health Perspect. 2002 Oct;110 Suppl 5(Suppl 5):689-94. doi: 10.1289/ehp.02110s5689.
Intracellular concentrations of essential metals are normally maintained within a narrow range, whereas the nonessential metals generally lack homeostatic controls. Some of the factors that contribute to metal homeostasis have recently been identified at the molecular level and include proteins that mediate import of essential metals from the extracellular environment, those that regulate delivery to specific intracellular proteins or compartments, and those that mediate metal export from the cell. Some of these proteins appear highly selective for a given essential metal; however, others are less specific and interact with multiple metals, including toxic metals. For example, DCT1 (divalent cation transporter-1; also known as NRAMP2 or DMT1) is considered to be a major cellular uptake mechanism for Fe(2+) and other essential divalent metals, but this protein also mediates uptake of Cd(2+), Pb(2+), and possibly of other toxic divalent metals. The ability of nonessential metals to interact with binding sites for essential metals is critical for their ability to gain access to specific cellular compartments and for their ability to disrupt normal biochemical or physiological functions. Another major mechanism by which metals traverse cell membranes and produce cell injury is by forming complexes whose overall structures mimic those of endogenous molecules. For example, it has long been known that arsenate and vanadate can compete with phosphate for transport and metabolism, thereby disrupting normal cellular functions. Similarly, cromate and molybdate can mimic sulfate in biological systems. Studies in our laboratory have focused on the transport and toxicity of methylmercury (MeHg) and inorganic mercury. Mercury has a high affinity for reduced sulfhydryl groups, including those of cysteine and glutathione (GSH). MeHg-l-cysteine is structurally similar to the amino acid methionine, and this complex is a substrate for transport systems that carry methionine across cell membranes. Once MeHg has entered the cell, some of it binds to GSH, and the resulting MeHg-glutathione complex appears to be a substrate for proteins that mediate cellular export of glutathione S-conjugates, including the apically located MRP2 (multidrug resistance-associated protein 2) transporter, a member of the adenosine triphosphate-binding cassette protein superfamily. Because other toxic metals also form complexes with endogenous molecules, comparable mechanisms may be involved in their membrane transport and disposition.
必需金属的细胞内浓度通常维持在狭窄范围内，而非必需金属一般缺乏稳态调控。最近，在分子水平上已鉴定出一些有助于金属稳态的因素，包括介导从细胞外环境导入必需金属的蛋白质、调节向特定细胞内蛋白质或区室输送的蛋白质，以及介导金属从细胞输出的蛋白质。其中一些蛋白质对特定的必需金属表现出高度选择性；然而，其他蛋白质的特异性较低，可与多种金属相互作用，包括有毒金属。例如，二价阳离子转运体1（DCT1；也称为NRAMP2或DMT1）被认为是细胞摄取Fe(2+)和其他必需二价金属的主要机制，但该蛋白质也介导Cd(2+)、Pb(2+)以及可能其他有毒二价金属的摄取。非必需金属与必需金属结合位点相互作用的能力对于它们进入特定细胞区室的能力以及破坏正常生化或生理功能的能力至关重要。金属穿过细胞膜并造成细胞损伤的另一个主要机制是形成整体结构模拟内源性分子的复合物。例如，长期以来人们已知砷酸盐和钒酸盐可与磷酸盐竞争转运和代谢，从而破坏正常细胞功能。同样，铬酸盐和钼酸盐可在生物系统中模拟硫酸盐。我们实验室的研究集中在甲基汞（MeHg）和无机汞的转运及毒性。汞对包括半胱氨酸和谷胱甘肽（GSH）在内的还原型巯基具有高亲和力。MeHg-L-半胱氨酸在结构上类似于氨基酸甲硫氨酸，并且该复合物是携带甲硫氨酸穿过细胞膜的转运系统的底物。一旦MeHg进入细胞，其中一些会与GSH结合，生成的MeHg-谷胱甘肽复合物似乎是介导谷胱甘肽S-共轭物细胞输出的蛋白质的底物，包括位于顶端的多药耐药相关蛋白2（MRP2）转运体，它是三磷酸腺苷结合盒蛋白超家族的成员。由于其他有毒金属也与内源性分子形成复合物，类似的机制可能参与它们的膜转运和分布。
