Liver copper storage and transport during development: implications for cytotoxicity.
Copper is an essential trace element for many biological processes. Its functions range from influencing specific gene expression to serving as a cofactor or prosthetic group for several enzymes. Intakes of copper at doses that exceed physiologic demands are normally met with efficient homeostatic mechanisms. Ceruloplasmin, albumin, and transcuprein, and to a lesser extent certain amino acids, are major copper-transporting constituents in circulating plasma. After its hepatic uptake, copper may be stored within hepatocytes, secreted into plasma, or excreted in bile. The biliary route represents the major excretory pathway of copper and largely accounts for its hepatic turnover. Copper retained by hepatocytes is mostly bound to specific metal-binding proteins, primarily metallothionein, or incorporated into several cuproenzymes. Copper incorporation into metallothionein and certain cuproproteins appears to require prior binding of copper to glutathione, thus defining a relation between copper metabolism and the intracellular availability of glutathione. Hepatic metallothionein concentrations can be modulated by dietary copper; changes in metallothionein and in copper status are significant throughout development. Binding of copper to metallothionein provides a temporary storage for cytoplasmic copper, preventing it from occurring as (potentially toxic) free ionic metal. In its unbound form, copper can generate hydroxyl radicals. Because metallothionein exhibits a high reactivity toward these radicals, it is increasingly recognized to play a protective role against copper-induced cytotoxicity. We discuss some of the possible toxicologic implications that may arise from changes in hepatic copper and metallothionein status during development.
Luza
S C
SC
Biochemical Pharmacology and Lipids Unit, Nutrition and Food Technology Institute, University of Chile, Santiago.
Speisky
H C
HC
D000818:Animals; D001646:Bile / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002570:Ceruloplasmin / Q000378:metabolism / Q000502:physiology; D003300:Copper / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D008668:Metallothionein / Q000378:metabolism / Q000502:physiology
D003300:Copper; D008668:Metallothionein; D002570:Ceruloplasmin; D005978:Glutathione