Ballatori N
Department of Biophysics, University of Rochester School of Medicine, New York 14642.
Drug Metab Rev. 1991;23(1-2):83-132. doi: 10.3109/03602539109029757.
The liver's pivotal role in the homeostasis of essential trace metals and detoxification of exogenous metals is attributed to its ability to efficiently extract metals from plasma, metabolize, store, and redistribute them in various forms either into bile or back into the bloodstream. Bidirectional transport across the sinusoidal plasma membrane allows the liver to control plasma concentrations and therefore availability to other tissues. In contrast, transport across the canalicular membrane is largely, but not exclusively, unidirectional and is a major excretory pathway. Although each metal has relatively distinct hepatic transport characteristics, some generalizations can be made. First, movement of metals from plasma to bile follows primarily a transcellular route. The roles of the paracellular pathway and of ductular secretion appear minimal. Second, intracellular binding proteins and in particular metallothionein play only indirect roles in transmembrane flux. The amounts of metallothionein normally secreted into plasma and bile are quite small and cannot account for total metal efflux. Third, metals traverse liver cell plasma membranes largely by facilitated diffusion, and by fluid-phase, adsorptive, and receptor-mediated endocytosis/exocytosis. There is currently no evidence for primary active transport. Because of the high rate of hepatocellular membrane turnover, metal transport via endocytic vesicles probably makes a larger contribution than previously recognized. Finally, there is significant overlap in substrate specificity on the putative membrane carriers for the essential trace metals. For example, zinc and copper share many transport characteristics and apparently compete for at least one common transport pathway. Similarly, canalicular transport of five of the metals discussed in this overview (Cu, Zn, Cd, Hg, and Pb) is linked to biliary GSH excretion. These metals may be transported as GSH complexes by the canalicular glutathione transport system(s). Unfortunately, none of the putative membrane carrier proteins have been studied at the subcellular or molecular level. Our knowledge of their biochemical properties is rudimentary and rests almost entirely on indirect evidence obtained in vivo or in intact cell systems. The challenge for the future is to isolate and characterize these putative metal carriers, and to determine how they are functionally regulated.
肝脏在必需微量元素的体内平衡及外源性金属解毒过程中发挥着关键作用，这归因于其能够有效地从血浆中摄取金属，进行代谢、储存，并以各种形式重新分配，要么排入胆汁，要么回到血液循环中。跨窦状隙质膜的双向转运使肝脏能够控制血浆浓度，进而控制其他组织对金属的摄取。相比之下，跨胆小管膜的转运在很大程度上（但并非完全）是单向的，是主要的排泄途径。尽管每种金属都有相对独特的肝脏转运特性，但仍可归纳出一些共性。首先，金属从血浆到胆汁的转运主要遵循跨细胞途径。细胞旁途径和胆小管分泌的作用似乎极小。其次，细胞内结合蛋白，特别是金属硫蛋白，在跨膜通量中仅起间接作用。正常情况下分泌到血浆和胆汁中的金属硫蛋白量相当少，无法解释总的金属外流。第三，金属主要通过易化扩散以及液相、吸附和受体介导的内吞/外排作用穿过肝细胞质膜。目前尚无原发性主动转运的证据。由于肝细胞质膜更新率高，通过内吞小泡进行的金属转运可能比以前认为的贡献更大。最后，必需微量元素假定的膜载体在底物特异性方面存在显著重叠。例如，锌和铜具有许多共同的转运特性，并且显然至少竞争一条共同的转运途径。同样，本综述中讨论的五种金属（铜、锌、镉、汞和铅）的胆小管转运与胆汁中谷胱甘肽（GSH）的排泄相关。这些金属可能作为GSH复合物通过胆小管谷胱甘肽转运系统进行转运。遗憾的是，尚未在亚细胞或分子水平上对任何假定的膜载体蛋白进行研究。我们对其生化特性的了解还很基础，几乎完全基于体内或完整细胞系统中获得的间接证据。未来的挑战是分离并鉴定这些假定的金属载体，并确定它们是如何受到功能调控的。
