Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.16.3.1 (ceruloplasmin)
 5,074 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a cDNA probe of the ceruloplasmin (CP) gene, a new restriction fragment length polymorphism (RFLP) was detected in inbred strains of rat with the restriction enzyme KpnI. The RFLP behaved as a codominant trait on a single autosomal locus. Two alleles of the CP gene, which were tentatively designated as CP-A and CP-B, were almost equally distributed in 10 inbred strains. These indicate that the RFLP of the CP gene is a useful marker locus of the rat. We utilized this CP gene polymorphism for the investigation of the pathogenesis of the aberrant hepatic copper metabolism in LEC mutant rat, since CP has a pivotal role in copper metabolism in the liver. Using backcross progenies originating from LEC and BN rats, we found that the CP gene is not associated with the excess hepatic copper accumulation and the deficiency in serum CP activity, both of which are congenital abnormal phenotypes exhibited in LEC mutant rat.
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PMID:A new restriction fragment length polymorphism of the ceruloplasmin gene in rat. 135 37

Both young (5 weeks old) and old (61-100 weeks old) hereditary hepatitis LEC rats showed a markedly low level of plasma ceruloplasmin (Cp) ferroxidase activity as compared with that of age-matched LEA and BN strain rats. This trait was genetically examined by the use of (BN x LEC) F1 hybrid and (F1 x LEC) backcross rats. The F1 hybrids never developed hepatitis and showed a similar level of Cp to that found in the parental BN rats. Among the backcross rats with about 1:1 segregation rate for hepatitis, affected rats had a remarkably decreased level of Cp, as found in LEC rats, whereas unaffected rats exhibited a similar level of Cp to that of BN, F1 and LEA rats. These results indicate that the low level of Cp is heritable in a single autosomal recessive mode in LEC rats. The observed tight link between the low Cp level and the hepatitis in LEC rats suggests that defective copper metabolism may be associated with the occurrence of hepatitis in LEC rats, since Cp is a copper-binding protein primarily involved in copper transport from the liver.
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PMID:Hereditary low level of plasma ceruloplasmin in LEC rats associated with spontaneous development of hepatitis and liver cancer. 190 93

The Cu concentration was about 40 times higher in the liver of LEC (Long-Evans with a cinnamon-like coat color) rats aged 77 days (227.5 +/- 21.6 micrograms/g liver) than in Fischer rats (5.2 +/- 0.1 microgram/g liver). However, in the kidney and brain of the LEC rats, Cu concentrations were lower than in these organs of the Fischer rats. Cu concentration in the hepatic metallothionein fraction was about 130 times higher in the LEC rats than in the Fischer rats. The LEC rats showed markedly low concentrations of Cu in the serum and bile. It seems likely that excretion of Cu from the liver into the bile and blood (as ceruloplasmin) is inherently lacking in the LEC rat.
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PMID:Copper metabolism in the LEC rat: involvement of induction of metallothionein and disposition of zinc and iron. 193 3

In 30- and 80-day-old LEC rats, hepatic Cu and Cu-metallothionein (MT) concentrations were much higher than those in control Fischer rats. The gross deposition was accompanied with enhancements of Zn and Fe concentrations. In LEC rats, more than half of the hepatic Cu was located in the cytosol fraction. Most of cytosolic Cu was bound to MT. In organs other than the liver, sharp depositions of Cu were not found. Both groups of LEC rats showed significantly low serum Cu concentrations and ceruloplasmin activity. The great accumulation of hepatic Cu with the increase of age is due to the inherent depression of the release of Cu from the liver. The deposition may be closely related to the onset of the sudden hepatitis observed in LEC rats.
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PMID:Copper metabolism in LEC rats aged 30 and 80 days old: induction of Cu-metallothionein and status of zinc and iron. 194 38

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.
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PMID:Harmful effect of administration of copper on LEC rats. 194 42

The LEC rat is a mutant inbred strain isolated from Long-Evans rats, which spontaneously develops hepatitis and hepatoma with high frequency. In this study, copper profiles of LEC rats, including copper concentration in the liver and concentrations of copper and ceruloplasmin in the serum, were investigated. It was found that copper accumulated in the liver of LEC rats immediately prior to the onset of hepatitis with a concentration of more than 50 times that of normal LEA rats, and serum concentrations of copper and ceruloplasmin decreased markedly, which resembled biochemically characteristic features of human Wilson's disease. Administration of d-penicillamine (100 mg/Kg/day p. o), a chelating agent, reduced the hepatic copper level and completely inhibited the development of hepatitis in LEC rats. Copper also accumulated in both cancerous and non-cancerous liver tissues of three 29-month old male LEC rats which had spontaneously developed hepatocellular carcinomas. These findings suggest that the hepatitis in LEC rats is caused by copper toxicity, and that the abnormal copper metabolism may be involved in hepatic carcinogenesis in the LEC rats. Therefore, it is considered that the LEC rat will provide a promising animal model for not only elucidating the pathogenesis of Wilson's disease and developing treatment strategies of the disease, but also for studying the role of copper in hepatic carcinogenesis.
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PMID:[Abnormal hepatic copper accumulation and its significance in LEC rats developing spontaneous hepatitis and hepatoma]. 195 41

The accumulation process of copper (Cu) in the liver and the following metabolic disorder of Cu were examined in LEC rats, a mutant strain which accumulates Cu with age and shows spontaneous acute hepatitis and/or hepatoma. Cu concentration in the liver of female rats was approximately 220 micrograms/g liver at 2 weeks of age, decreased to 100 micrograms/g liver at 4-6 weeks, and then started to increase with age linearly to the highest concentration of 250 micrograms/g liver at 16 weeks. Although the Cu level expressed by concentration (microgram/g liver) decreased during weaning, it increased linearly with age when it was expressed by content (mg/liver), indicating a constant and preferential accumulation of Cu in the liver. Cu concentration stopped increasing at 16 weeks in the liver, followed by a sudden decrease to 1/2 the highest level. Biological markers (serum lactate dehydrogenase and glutamic-oxaloacetic transaminase activities) for liver damage started to increase, together with the appearance of signs of jaundice, when Cu attained the highest concentration. Distributions of Cu and zinc (Zn) in the supernatant fraction of the liver indicated that both metals were mostly distributed to metallothionein (MT) and, to a small extent, to superoxide dismutase on a gel filtration column throughout the course of the experiments. Serum Cu concentration started to increase in a form of ceruloplasmin, together with serum marker enzyme activities for liver damage. Cu concentration in the kidneys also started to increase after the increase of serum Cu. The results indicate that Cu accumulates in the form of MT in the liver of LEC rats to a maximum level of approximately 250 micrograms/g liver, and then decreases suddenly with the onset of acute hepatitis. The maximum level seems to be related to the capacity of MT synthesis, and acute hepatitis is assumed to occur when Cu accumulates beyond the capacity. Serum Cu started to increase, from the abnormally low level, when the metal accumulated beyond the capacity of MT synthesis in the liver, and it was partly reabsorbed by the kidneys and the rest was excreted into urine. Changes in iron and zinc levels were determined and discussed in relation to those of Cu.
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PMID:Copper metabolism leading to and following acute hepatitis in LEC rats. 771 95

Copper incorporation into ceruloplasmin during ceruloplasmin synthesis was studied by comparing LEC and control rats. Major 132 and 136 kDa ceruloplasmins were found in microsomes and the Golgi apparatus, respectively, isolated from liver homogenates of LEC and control rats. Copper analysis showed that no copper was detected in the ceruloplasmin in the microsomes of either rat. Copper was present in ceruloplasmin in the Golgi apparatus and serum of controls, while it was not detected in ceruloplasmin in the Golgi apparatus and serum of the LEC rat. These results indicate that copper is incorporated into ceruloplasmin in the Golgi apparatus of normal hepatocytes. LEC rats fail to incorporate copper into ceruloplasmin in the Golgi apparatus.
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PMID:Failure of copper incorporation into ceruloplasmin in the Golgi apparatus of LEC rat hepatocytes. 772 56

Copper (Cu) and zinc (Zn)-binding superoxide dismutase (Cu,Zn-SOD) is synthesized always in a form of holo-protein in the liver of LEC rats, a genetically disordered mutant strain in Cu metabolism which accumulates Cu in a form bound to metallothionein (MT). On the other hand, ceruloplasmin (Cp) is synthesized in the liver and excreted into the blood plasma mostly as an apo-protein before the onset of acute hepatitis, and then holoform at the onset of jaundice. Thus, Cu is supplied differentially between Cp and SOD, and at different times, i.e., before and at the onset of acute hepatitis. Availability of Cu to apo-SOD was examined to explain the mechanisms for the differential supply of Cu among three different Cu forms; i) cuprous ion bound to glutathione, ii) free cupric ion, and iii) cuprous ion bound to MT. Cu was transferred to SOD from the three Cu complexes though MT-bound Cu was a less efficient Cu source to apo-SOD. The results indicate that SOD is always present in a holo-form in LEC rats because even MT-bound Cu can be supplied to SOD, while Cp is present in an apo-form because Cu is sequestered to MT and not available in free ionic forms in LEC rats before the onset of acute hepatitis.
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PMID:Direct transfer of copper from metallothionein to superoxide dismutase: a possible mechanism for differential supply of Cu to SOD and ceruloplasmin in LEC rats. 785 Feb 52

Recently it was found that the clinical features of the LEC rat closely resemble those of human Wilson's disease. One of the characteristics of the animal is low levels of serum ceruloplasmin. Therefore, by using LEC rats, we attempted to define molecular basis of the deficiency in active site of ceruloplasmin in Wilson's disease patients. We made 3 monoclonal antibodies, ID2 against active site of ceruloplasmin, ID1 against inactive site of ceruloplasmin, and the remaining one against metallothionein. Using these monoclonal antibodies, we examined immunohistochemical stainings of LEC rat liver tissues, and compared them with those of LEA rats, as a control. ID1 stained the hepatocytes of both LEA and LEC rats, whereas ID2 stained LEA rat hepatocytes only. The results indicated that the ceruloplasmin secreted by LEC rat hepatocytes is mostly in inactive form. The antibody against metallothionein stained LEA rat hepatocytes only. This finding may also indicate that LEC rat hepatocytes express less amount of metallothionein than those of LEA rats.
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PMID:Lack of copper binding sites in ceruloplasmin of LEC rats with abnormal copper metabolism. 828 Jan 28


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