metallothionein and Jaundice

Rats of Long-Evans Cinnamon (LEC) strain were used as a hepatorenal syndrome model of fulminant Wilson's disease. Copper levels in the kidneys increased markedly from 16 to 126 microg Cu/g from 12 to 16 weeks, and remained at the same level at 16 and 19 weeks when the rats suffered from severe renal dysfunction and also at 20 weeks in some other normal rats. The above findings imply that the renal dysfunction may have been induced independently of the copper level in the kidneys. The present study suggested the following mechanism: immediately after copper-induced hepatic dysfunction, plasma copper-metallothionein (CuMT), which was released from the liver, became elevated. The elevation was closely related to the increases in alkaline phosphatase, glucose and amino acids, all in the urine. The above findings suggest that plasma CuMT, which was released from the liver into the blood upon copper-induced hepatic dysfunction, was subsequently filtered at the glomeruli due to its smaller molecular weight, and then caused dysfunction of the brush border membrane of the renal proximal tubules probably after splitting into radical copper and amino acids in acidic vesicles close to the membrane. The critical concentration of plasma CuMT required to induce renal dysfunction was estimated as 1 microg Cu/l.

Topics: Animals; Copper; Disease Models, Animal; Hepatolenticular Degeneration; Hepatorenal Syndrome; Jaundice; Kidney; Liver; Male; Metallothionein; Rats; Rats, Long-Evans

LEC rats (Long-Evans with a cinnamon-like coat color) have a genetical defect in Cu metabolism. Male LEC rats aged 10 weeks were injected ip with TTM at a dose of 5 or 10 mg/kg body weight for 8 consecutive days and killed one day after the last injection. Cu that had accumulated in the liver at a concentration of 251 micrograms/g liver was decreased to 82.7 or 74.3 micrograms/g liver respectively, by the treatment. Although most of Cu was bound to MT as a soluble form before TTM treatment, the metal remaining in the liver after the treatment was present almost exclusively in the non-soluble fraction. Zinc (Zn) present, bound to MT before the treatment, was also partly removed from the liver by TTM, and the Zn remaining in the liver after the treatment was revealed to be bound to MT (Zn-MT) by high performance liquid chromatography-atomic absorption spectrophotometry. Iron (Fe) in the liver was not affected by TTM treatment. Cu in the kidneys and spleen increased by TTM treatment, while Zn and iron were not affected. Treatment of LEC rats with severe jaundice effectively cured the animals from otherwise lethal signs by only two ip injections of TTM at a dose of 10 mg/kg body weight.

Topics: Animals; Copper; Iron; Jaundice; Liver; Male; Metallothionein; Molybdenum; Rats; Rats, Inbred Strains; Zinc

Copper (Cu) accumulating in the liver of LEC (Long-Evans with a cinnamon-like coat color) rats due to a hereditary metabolic disorder is assumed to cause acute hepatitis with severe jaundice or chronic hepatitis leading to cancer. Changes in concentrations and distributions of Cu, zinc and iron in the liver of LEC rats were determined to find the relationship between the chemical forms and the toxicity. Female rats after delivery were used because of high susceptibility to acute hepatitis. They were divided into four stages according to the development of jaundice. Cu concentrations in the whole liver and the supernatant decreased with development of jaundice. Distribution profiles of Cu, zinc, iron and sulfur on a gel filtration column by HPLC-ICP showed that Cu in the liver supernatant was mostly bound to metallothionein (MT) before jaundice (stage 1), high molecular weight proteins and MT at the beginning of jaundice (stages 2 and 3), and then mostly to MT at severe jaundice (stage 4) though the concentration of Cu at this stage was decreased to about 50% of stage 1. The results suggest that Cu accumulating as MT in the liver is liberated drastically after exceeding the capacity of MT synthesis, and the liberated Cu causes acute hepatitis.

Topics: Animals; Copper; Female; Hepatitis, Animal; Iron; Jaundice; Liver; Metallothionein; Rats; Rats, Inbred Strains; Sulfur; Zinc

Recently, copper (Cu) was found to be unusually accumulated, suggesting the induction of metallothionein (MT) in the liver of LEC rats (Long-Evans rats with a cinnamon-like coat color), which develop spontaneous jaundice with hereditary hepatitis. Thus, the direct relationship between the unusual Cu accumulation and the induction of Cu-MT was investigated by giving LEC rats Cu-overloaded or Cu-deficient diets. Results based on the determinations of Cu and MT levels in several organs, as well as the gel-filtration profiles of the cytosols of liver homogenates, showed that dietary Cu induced Cu-MT and development of hepatic injury associated with jaundice.

Topics: Animals; Copper; Cytosol; Hepatitis, Animal; Jaundice; Liver; Metallothionein; Rats; Rats, Mutant Strains

When four male LEC rats aged 80 days old were given 3.0 mg/kg of Cu once every day for 3 days, all rats showed severe jaundice, and two of them died within 48 hr after the final dose. In Fischer rats given Cu, jaundice or death was not found. With the injection of Cu, the Cu metabolism of Fischer and LEC rats showed different responses. In particular, the concentration of hepatic Cu increased only slightly in LEC rats. Furthermore, LEC rats did not respond to the release of ceruloplasmin to the blood and of Cu to the bile. These results suggest that Cu was very dangerous for LEC rats because of its gross accumulation over the level of homeostasis.

Topics: Animals; Ceruloplasmin; Chemical and Drug Induced Liver Injury; Copper; Cytosol; Female; Jaundice; Kidney; Liver; Male; Metallothionein; Rats; Rats, Inbred Strains