Excessive Accumulation of Hepatic Copper in LEC Rats Aged 80 Days without Hepatitis and 130 Days with Hepatitis

Abstract

The Cu concentration was about 40 and 60 times higher in the liver in Long-Evans with a cinnamon-like coat color (LEC) rats aged 80 days (without hepatitis) and 130 days (with hepatitis), respectively than in the liver in Fischer rats. Most hepatic Cu was recovered in the cytosol fraction. Furthermore, about 96% and 84% of the cytosolic Cu was found in the metallothionein region on a Sephadex G-75 column in LEC rats aged 80 and 130 days, respectively. The hepatic metallothionein concentration was about 130 to 140 times higher in LEC rats than in Fischer rats when the concentration was expressed as metallothionein-bound Cu. Three forms of Cu-metallothionein were isolated by DEAE-cartridge. Although the concentration of hepatic Cu-metallothionein and its composition of polymorphic form were not changed greatly in hepatitis phase (in the 130-day-old LEC rats), activities of serum enzymes, aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) were increased significantly. The LEC rat showed a significantly low concentration of biliary Cu and markedly low activity of ceruloplasmin (as ferroxidase). Serum Cu showed a low concentration in the 80-day-old LEC rats, but recovered to the control level in the 130-day-old LEC rats. The abnormal accumulation of Cu may be due to the inherent reduction of excretion of Cu into the bile and blood. Such deposition may be a trigger for the onset of the spontaneous hepatitis occurring at 90-120 days after birth and for the onset of hepatoma later.

Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats.

“…The maximum level at week 15 in the RD group was significantly higher than that in the ID group ( P Ͻ 0.01), suggesting that more copper was released as the result of fulminant hepatitis. The serum copper levels in both groups showed gradual decreases after week 20, compatible with the previous finding that the synthesis of metallothionein was sufficiently induced to chelate copper after this period (30). Serum iron concentrations in the RD group rapidly elevated immediately after birth to form a peak at week 15, and then a transient depletion again followed a peak at week 20 which gradually became a plateau maintaining relatively high levels, suggesting that iron absorption is increased in LEC rats (Fig.…”

“…Moreover, why hemolysis never occurred after 20 wk can be understood by reasoning that free copper was accommodated by newly induced metallothionein (30). Further evidence for the indirect involvement of copper in abrupt hepatic injury via induction of hemolysis was clearly presented by the experiment with the ID group; hemolytic episodes did occur in these rats.…”

Manifestations of copper excess

“…These rats rapidly accumulate copper in the liver and develop fulminant hepatitis at Ϸ4 mo of age. The degree of liver damage is much greater than that observed in most breeds of laboratory rats at equivalent liver copper concentrations, yet most of the liver copper in LEC rats is bound to metallothionein (28). It may be that the hepatotoxic effects of copper in LEC rats are associated with the nonmetallothionein fraction or with the fact that most of the metallothionein is present in the cytosol.…”

LEC rats: An overview of recent findings

“…Levels of iron concentrations in the liver of 18-week-old LEC rats reached up to three times those found in Wistar rat livers of the same age [6]. This level, however, is not so high when compared to a copper accumulation that is 40-60 times higher in LEC rat liver, as compared to the Fisher rat liver as a control [7]. In contrast, levels of manganese in LEC rat liver are < 1 ⁄10 levels of Wistar rat liver [6].…”