Zinc Toxicity: From “No, Never” to “Hardly Ever” Eve A. Roberts  Gastroenterology  Volume 140, Issue 4, Pages 1132-1135 (April 2011) DOI: 10.1053/j.gastro.2011.02.028 Copyright © 2011 AGA Institute Terms and Conditions

Figure 1 Selected features of zinc disposition in hepatocytes and possible mechanisms of hepatotoxicity in Wilson disease. A doublet of hepatocytes is shown with a bile canaliculus (BC) demarcated by 2 tight junctions (TJ). Zinc uptake pathways include ZIP10 and ZIP14, both on the plasma membrane. Once inside the hepatocyte, zinc (green circle) is associated with numerous intracellular proteins, and extremely little is available as “free” zinc in the cytoplasm. MTF-1 (green triangle) has regulatory functions sensitive to intracellular zinc concentrations. Zinc is mainly associated with metallothioneins (red spiny stars) that serve also as a reservoir for copper (red circles). Zinc exits the hepatocyte via transporters in the ZnT family. When zinc concentrations are elevated, mitochondrial damage may ensue; oxidant stress occurs; gene regulation may be affected adversely (N, nucleus). The copper uptake pathway via CTR1 plus association with the copper-chaperone ATOX1 (light blue squares) is illustrated: in the absence of functional ATP7B, the Wilson ATPase, copper excretion pathways are dysfunctional and copper accumulates. Gastroenterology 2011 140, 1132-1135DOI: (10.1053/j.gastro.2011.02.028) Copyright © 2011 AGA Institute Terms and Conditions