Hepatocytes copper

Excess copper is the result of either excessive copper absorption or ineffective copper excretion. The most common diseases associated with copper excess are (1) Wilson s disease, a genetic disease resulting in mutations in the Wilson s disease P-type ATPase and excessive hepatocyte copper accumulation (2) renal disease, in patients on hemodialysis due to kidney failure when dialysate solutions become contaminated with excess copper and (3) biliary obstruction. Excessive use of copper supplements may also contribute to copper toxicity and is clinically manifested by severe anemia, nausea and vomiting, abdominal pain, and diarrhea. 

Wilson s disease is another autosomal recessive disease leading to cirrhosis. Protein abnormalities result in excessive copper deposition in body tissues. The faulty protein is responsible for facilitating copper excretion in the bile, so copper accumulates in hepatic tissue. High copper levels within hepatocytes are toxic, and fibrosis and cirrhosis may develop in untreated patients. Those with Wilson s disease usually present with symptoms of liver or neurologic disease while still in their teens. 

Goldfischer, S., B. Schiller, and I. Sternlieb. 1970. Copper in hepatocyte lysosomes of the toad, Bufo marinus L. Nature 228 172-173. 

Roncero, V., E. Duran, F. Soler, J. Masot, and L. Gomez. 1992. Morphometric, structural, and ultrastructural studies of tench (Tinea tinea L.) hepatocytes after copper sulfate administration. Environ. Res. 57 45-58. 

Stacey, N.H. and C.D. Klaassen. 1981. Copper toxicity in isolated rat hepatocytes. Toxicol. Appl. Pharmacol. 58 211-220. 

Figure 18.4 Proteins involved in copper uptake, incorporation into ceruloplasmin and biliary excretion in normal and Wilson s disease hepatocytes. (From Crichton and Ward, 2006. Reproduced with permission from John Wiley Sons., Inc.)...

Pharmacology Wilson disease (hepatolenticular degeneration) is an inherited metabolic defect resulting in excess copper accumulation, possibly because the liver lacks the mechanism to excrete free copper into the bile. Hepatocytes store excess copper, but when their capacity is exceeded, copper is released into the blood and is taken up into extrahepatic sites. Treat this condition with a low copper diet and chelating agents that bind copper to facilitate its excretion from the body. Trientine is a chelating compound for removal of excess copper from the body. 

Feng, Q., Boone, A.N. and Vijayan, M.M. (2003) Copper impact on heat shock protein 70 expression and apoptosis in rainbow trout hepatocytes, Comparative Biochemistry and Physiology, Part C 135 (3), 345-355. 

Zhu, J.-H., and Lei, X. G. Double null of selenium-glutathione peroxidase-1 and copper,zinc-superoxide dismutase enhances resistance of mouse primary hepatocytes to acetaminophen toxicity. Exp. Biol. Med. 231 545-552, 2006. 

Several papers utilizing 3 mm probe capabilities were also published that delved into the area of protein structures. Hepatocyte nuclear factor 4 was studied by a group lead by Williams.155 It is interesting to note that a 2.7 A X-ray study showed a fatty acid in the pocket of HNF4y. Gas chromatography coupled mass spectrometry (GC/MS) and 3 mm NMR studies of extracts from purified HNF4x led to the identification of mixtures of saturated and crs-monounsaturated Ci4 to Qg fatty acids. Bertini and co-workers156 utilized 3 mm probe capabilities in the determination of the solution structure of CopC, a cupredoxin-like protein involved in copper homeostasis. 

Wilson disease is an autosomal recessive disorder of copper transport (Figure 1). It results in the toxic accumulation of copper in various tissues, but mainly in the liver, kidney, and brain. Wilson disease occurs worldwide with an average prevalence of about 1 in 30 000 in most populations. The age of onset for Wilson disease is variable and can extend from 3-4 years into the mid-50s. There are three phases in the progression of the disease. In the first phase, copper accumulates in the cytoplasm of hepatocytes. As more copper is absorbed, in the second phase the increased concentration of... 

Transferrin is mainly synthesized in the hepatocytes. There are about 20 known variants. Iron is transported by transferrin (approx. 30% of transferrin is saturated with iron). With the help of a membrane receptor, the iron-transferrin complex is taken up and released in the liver cell, where it is immediately bound (because of its toxicity) to ferritin. The liver cells take up iron predominantly from transferrin, to a lesser degree also from haptoglobin, haemopexin, lactoferrin and circulating ferrin. Transferrin, which is mainly formed in the hepatocytes, may also bind and transport, in decreasing order, chromium, copper, manganese, cobalt, cadmium, zinc and nickel. The half-life of transferrin is 1 - 2 hours, which is very short in view of its total blood concentration of 3-4 mg. Approximately 0.4 g ferritin iron is stored in the liver. In the case of transferrin deficiency, its bacteriostatic and fungistatic effects are also reduced. Transferrin without iron saturation is known as apo-transferrin. (31, 66, 67)... 

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