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PubMed1999

Identification of the zinc-binding protein specifically present in male rat liver as carbonic anhydrase III.

A zinc (Zn)-binding protein that is present specifically in the livers of male adult rats was detected by HPLC with in-line detection by mass spectrometry (ICP MS). The Zn-binding protein was purified on Sephadex G-75 and G3000SW HPLC columns. and was identified as carbonic anhydrase III (CAIII) based on the amino acid sequence of a peptide obtained on lysyl endopeptidase digestion. CAIII is expressed as one of the major Zn-binding proteins in the livers of male rats in an age-dependent manner, a comparable amount of Zn to that of copper, Zn-superoxide dismutase (Cu,Zn-SOD) being bound to CAIII at 8 weeks of age. Castration at 4 or 8 weeks of age was shown to reduce Zn bound to CAIII to 47.5% of the sham-operated control level, suggesting that the sex-dependent expression of CAIII is partly regulated by a sex hormone, androgen. The concentration of CAIII in the livers of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease, was also estimated as Zn bound to CAIII and shown to be lower than that in Wistar rats before the onset of hepatitis. The concentration of CAIII was decreased specifically by repeated injections of cupric ions without the Cu,Zn-SOD concentration being affected.

Animals↗

PubMed2003

Gene expression in the liver of Long-Evans cinnamon rats during the development of hepatitis.

The Long-Evans cinnamon (LEC) rat, an authentic model for Wilson disease, is characterized by a mutation in the Atp7b gene leading to a defective copper excretion and, as a consequence, to an accumulation of the metal in the liver and copper-associated hepatotoxicity. In the present communication expression profiles of genes in the liver from wild-type Long-Evans agouti (LEA) and LEC rats at different stages of copper accumulation and liver disease were investigated. Disease states were defined according to serum aspartate aminotransferase activity and bilirubin levels in serum and from histopathology of the liver. Gene expression was determined with the Affymetrix RTU34 oligonucleotide array covering 1031 genes. Compared to the LEA rat, the nondiseased LEC rat with already increased hepatic copper level showed an enhanced expression of genes, particularly related to oxidative stress and DNA damage. During the progression of the liver disease, in particular genes related to oxidative stress, DNA damage, apoptosis and inflammation with acute-phase reaction were upregulated.

Acute-Phase Reaction↗

PubMed2006

Development of liver regenerative therapy using glycoside-modified bone marrow cells.

Several recent studies have reported that bone marrow cells (BMCs) have the ability to generate functional hepatocytes. However, the efficiency at which BMC transplantation generates functional hepatocytes is rather low. We assumed that if BMCs accumulated directly in liver, the functional BMC-derived hepatocytes should increase efficiently. We tried to increase the accumulation of BMCs directly in liver through the interaction between hepatic asialoglycoprotein receptor and desialylated BMCs. Desialylated BMCs were produced with treatment of neuraminidase. Desialylated BMCs that expressed green fluorescent protein (GFP) were injected into Long Evans Cinnamon (LEC) rats, a human Wilson's disease model, intravenously. At 3 and 5 months after transplantation, GFP-expressing hepatocyte nodules appeared in the liver of these BMC-transplanted LEC rats. These findings suggest that the functional BMC-derived hepatocytes can be generated by the direct accumulation of BMCs and that this strategy is new BMC therapy for liver regeneration.

Animals↗

PubMed2005

Fe(II)/Cu(I)-dependent P-type ATPase activity in the liver of Long-Evans cinnamon rats.

This study examined Fe(II)-dependent ATPase activity in OTG (octylthioglucoside) -treated microsomes isolated from Wistar and LEC rats. The ATPase activity of the liver OTG-microsomes from Wistar rats increased sharply in the 5-150 microM range of Fe(II) with a K0.5 value of 23.9+/-3.6 microM, while the activity of LEC rat liver microsomes increased with increasing Fe(II) up to 500 microM with a K0.5 value of 64.4+/-8.1 microM. The K0.5 values for Fe(II)-dependent ATPase activity of spleen OTG-microsomes were nearly identical at 59.3 microM in the Wistar rat and 63.7 microM in the LEC rats with a similar level of activity at each Fe(II) concentration in both strains of animals. These results indicated that there are two types of Fe(II)-dependent ATPase with different Fe(II) sensitivity, a high sensitive (H) and a low sensitive (L) type, and that the H-type activity was specific to the liver. The H-type activity was, however, deficient in the liver of LEC rats that accumulate copper and iron in hepatocytes as a result of mutations in the Wilson's disease protein (WNDP). On the basis of these results, together with the similarity in optimal conditions required for full activity of the enzyme, we conclude that the Fe(II)-dependent ATPase (H-type) and WNDP may be identical.

Adenosine Triphosphatases↗

PubMed2006

Lentiviral gene transfer ameliorates disease progression in Long-Evans cinnamon rats: an animal model for Wilson disease.

OBJECTIVE: Wilson disease is a copper storage disorder caused by mutations in the ATP7B gene leading to liver cirrhosis. It has previously been shown that lentiviral vectors can govern an efficient delivery and stable expression of a transgene. The aim of this pilot study was to prove the principle of a lentiviral gene transfer in the Long-Evans cinnamon (LEC) rat, an animal model of Wilson disease. MATERIAL AND METHODS: LEC rats were treated either by systemic application of lentiviral vectors or by intrasplenic transplantation of LEC-rat hepatocytes lentivirally transduced with ATP7B. The ATP7B gene expression was analyzed by RT-PCR and immunofluorescence analysis. The therapeutic effect was assessed by analysis of liver histology, serum ceruloplasmin oxidase activity, and liver copper content. RESULTS: Hepatic expression of the transgene was detected at different time-points post-treatment and lasted for up to 24 weeks (end of experiment). Liver copper levels were lowered in all treatment groups compared to untreated LEC rats. Twenty-four weeks after treatment, the area of the examined liver-tissue sections occupied by fibrosis was 48.3-57.9% in untreated LEC rats and 10.7-19.8% in rats treated with cell therapy. In systemically treated rats, only small fibrous septa could be observed. CONCLUSIONS: These data prove for the first time that lentiviral ATP7B gene transfer is feasible in Wilson disease. In our pilot study the systemic approach was more promising in ameliorating disease progression than the transplantation of lentivirally transduced hepatocytes.

Adenosine Triphosphatases↗

PubMed2002

Chances and shortcomins of adenovirus-mediated ATP7B gene transfer in Wilson disease: proof of principle demonstrated in a pilot study with LEC rats.

BACKGROUND & AIMS: Wilson disease (WD) is an autosomal recessively inherited copper storage disease due to mutations in the ATP7B gene. It results in impaired biliary copper excretion followed by liver injury leading to cirrhosis. In parallel, copper accumulates in other tissues e. g. basal ganglia of the brain inducing motoric disorders. Phenotypical cure of Wilson disease by liver transplantation raised the question whether gene therapy may represent a successful alternative treatment procedure. To examine the principle feasibility of this approach we investigated the effects of gene transfer using an adenoviral vector construct expressing the human ATP7B cDNA in an established rodent model for WD, the Long-Evans Cinnemon rat (LEC). METHODS: Transduction efficiency was assessed by RT-PCR, Western blot and immunofluorescence analysis. The therapeutic effect was estimated by analyzing holoceruloplasmin and its ferroxidase activity in serum, and the copper content of excrements. Changes in copper homeostasis were determined by positron emission tomography (PET). RESULTS: Successful, but temporary gene transfer was clearly detectable on RNA and protein levels. In parallel the temporary therapeutic effect was documented by restoration of serum holoceruloplasmin and of its ferroxidase activity. Additionally the Ad-ATP7B treated LEC rat revealed a higher (64)Cu content in stool. PET was able to visualize differences in (64)Cu distribution between wild type and LEC rats, indicating its principle usefulness as analytical tool. CONCLUSION: The data demonstrate proof of principle of successful gene therapy in an experimental model of WD. As a consequence of successful but only transient therapeutic effect of adenoviral gene transfer we can now focus more efficient and permanent gene transfer strategies.

Adenosine Triphosphatases↗

PubMed2005

Whole animal copper flux assessed by positron emission tomography in the Long-Evans cinnamon rat--a feasibility study.

Copper is an essential trace element. However, excess copper can lead to oxidation of biomolecules and cell damage and copper levels must be carefully controlled. While copper homeostasis has been studied extensively at the cellular level, short-term body copper fluxes are poorly understood. Here, we assessed for the first time the feasibility of measuring whole body copper flux by positron emission tomography, using 64Cu. A comparative approach comparing the Long-Evans cinnamon (LEC) rat to the wild type was chosen. LEC rats are an accepted model for Wilson disease, an inherited disorder of copper excretion in humans. In LEC rats as well as in Wilson patients, the copper transporting ATPase, ATP7B, is defective. This ATPase is primarily expressed in the liver and serves in copper secretion via the bile. Dysfunction of ATP7B leads to accumulation of copper in the liver. A control and an LEC rat were transgastrically injected with 10 microg of 64Cu and the copper flux followed for three hours by whole animal PET and concomitant collection of bile, as well as the analysis of tissue following tomography. As seen by PET, the administered copper was largely trapped in the stomach and the proximal intestine, and without a significant difference between control and LEC rat. Due to an insufficient dynamic range of the PET technology, copper which was systemically absorbed and primarily transported to the liver could only be followed by sampling and by beta-counting. Biliary copper excretion ensued after 15 min in the control rat, but was absent in the LEC rat. Biliary excretion reached saturation one hour after copper administration. The trapping of orally administered copper in the gastrointestinal tract may be an important mechanism to prevent copper toxicity under conditions of a sudden, excessive copper load, which cannot be alleviated by increased biliary secretion. This trapping does however limit the utility of PET to measure whole animal copper flux.

Adenosine Triphosphatases↗

PubMed2002

99mTc-mebrofenin scintigraphy for evaluating liver disease in a rat model of Wilson's disease.

UNLABELLED: The purpose of this study was to establish whether (99m)Tc-mebrofenin could noninvasively assess liver function in Wilson's disease. METHODS: Long-Evans Cinnamon (LEC) rats, which reproduce Wilson's disease with copper toxicosis, and their normal counterparts, Long-Evans Agouti (LEA) rats, were studied. Scintigraphic findings were correlated with biliary mebrofenin excretion and residual organ counts and with hepatic copper content, histology, copper excretion capacity, and liver test results. RESULTS: Serum alanine aminotransferase (ALT) levels were elevated in some LEC rats, whereas serum bilirubin levels were normal. Liver histology was normal in LEA rats, whereas LEC rats showed multiple abnormalities. Mebrofenin was incorporated rapidly in LEA rats, with a mean time to peak liver activity of 80 +/- 30 s, followed by prompt biliary excretion of the tracer. In LEC rats, the mean time to peak activity, 283 +/- 190 s, was significantly longer (P = 0.001). The time to half of peak activity, indicating tracer clearance, was significantly greater in LEC rats than in LEA rats (1,825 +/- 1,642 s vs. 524 +/- 82 s, P = 0.002). Hepatic mebrofenin handling correlated with hepatic copper content, histologic grade, copper excretion capacity, and serum ALT. CONCLUSION: Correlation of (99m)Tc-mebrofenin handling with liver morphology, function, and copper accumulation in LEC rats suggests that mebrofenin scintigraphy can be useful for noninvasively monitoring disease progression and therapeutic response in Wilson's disease. Although the data were obtained in an animal model of Wilson' disease, these biochemical parameters likely reflect liver damage in general, suggesting that there may be a role for mebrofenin scintigraphy in other chronic liver diseases as well.

Alanine Transaminase↗

PubMed2005

A new strain of rat for functional analysis of PINA.

Long Evans cinnamon (LEC) rat is an animal model for human Wilson disease (WD) due to a deletion in Atp7b, the copper transporter defective in WD patients. Previously, we have demonstrated presence of an alternative product termed PIneal Night-specific ATPase (PINA) generated by an intronic promoter in Atp7b gene. Analysis of LEC rat in this study demonstrates that PINA is absent in the LEC pineal establishing its usefulness for investigating PINA function. Studies of the LEC pineal, however, revealed an additional defect in serotonin N-acetyltransferase (NAT), the key enzyme in melatonin production. Linkage studies confirm that the NAT phenotype is entirely independent of PINA mutation in the pineal gland of LEC rats, and sequence analysis demonstrates that NAT defect is due to a point mutation in NAT coding region. In addition, we demonstrate that the cinnamon coat color of the LEC rat is unlinked to PINA and NAT deficiencies in these animals. To facilitate further functional analysis of PINA in pineal physiology, we crossed LEC rats with PVG rats that are wildtype for PINA, NAT and coat color, and obtained rats that are defective only in PINA/Atp7b locus (termed LPP rats) and normal for NAT activity and coat color. Furthermore, we have identified the deletion breakpoint of Atp7b gene in LPP rats, which allows simplified genotyping of mutant animals. The separation of PINA mutation from both NAT and coat color mutations in the new LPP rats will permit better functional studies of PINA in pineal circadian physiology.

Adenosine Triphosphatases↗

PubMed2000

Storage of lipid droplets in and production of extracellular matrix by hepatic stellate cells (vitamin A-storing cells) in Long-Evans cinnamon-like colored (LEC) rats.

LEC rats spontaneously develop hepatocellular carcinoma with cholangiofibrosis after chronic hepatitis, but the mechanism of development of the hepatic injury is not clear. To investigate the role of hepatic stellate cells in induction or suppression of hepatic fibrosis, we morphologically examined the liver of LEC rats. Accumulation of copper was analyzed by the Danscher-Timm's sulfide-silver method. Histopathological changes were evaluated by hematoxylin and eosin staining, and by Masson's trichrome method. Activated stellate cells were identified by immunostaining method for alpha-smooth muscle actin. Cytological alterations of the stellate cells were investigated by transmission electron microscopy. To evaluate the lipid content in the stellate cells, we analyzed the area of lipid droplets of the cells by morphometric analysis. Also for evaluation of the changes in the number of stellate cells, the numbers of nucleated stellate cells and parenchymal cells were counted and statistically analyzed. Hepatic parenchymal cells showed excessive accumulation of copper at 5 weeks of age. Submassive necrosis was observed at 19 weeks of age. The liver of LEC rats 1.5 years of age showed cholangiofibrosis and subcellular injury of hepatic parenchymal cells. However, no diffuse hepatic fibrosis was observed in the liver, and hepatic stellate cells around the regions of cholangiofibrosis were negative for alpha-smooth muscle actin. The area of lipid droplets of a stellate cell in the liver of LEC rats was 1.6 to 1.8 times as large as that of normal Wistar rats. The hepatic stellate cells did not participate in the accumulation of collagen fibers around themselves when the cells contained a large amount of vitamin A-lipid droplets, even though the development of hepatic lesions was in progress. Our present data are consistent with our previous hypothesis that there is an antagonistic relationship between the storage of vitamin A and the production of collagen in stellate cells.

Actins↗

PubMed2004

Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease.

BACKGROUND/AIMS: Tetrathiomolybdate (TTM) is a potent copper-chelating agent that has been shown to be effective in Wilson disease patients with neurological symptoms. Here, we investigate the potential use of TTM in treating the acute hepatic copper toxicosis in Long-Evans Cinnamon (LEC) rats, an authentic model for Wilson disease. METHODS: After the onset of acute hepatitis, LEC rats were treated once with 10 mg TTM/kg. After 1 and 4 days, parameters of liver toxicity and the subcellular distribution and binding of copper and iron were studied. RESULTS: In 11 out of 12 rats TTM rapidly improved acute hepatitis. Hepatic copper decreased through removal from cytosolic metallothionein and lysosomal metallothionein polymers. The remaining lysosomal copper forms a metallothionein-copper-TTM complex. In an almost moribund rat, however, TTM caused severe hepatotoxicity with fatal outcome. CONCLUSIONS: TTM is effective in treating acute hepatitis in LEC rats when applied before the animals become moribund. TTM appears to act by removing the presumable reactive copper associated to lysosomal metallothionein polymers. The remaining lysosomal copper seems to be inactivated by forming a complex with TTM. Moreover, TTM removes copper from cytosolic copper-containing metallothionein. As a consequence, metallothionein is degraded and the uptake of copper-metallothionein into the lysosomes and the formation of the metallothionein polymer associated copper is reduced.

Acute Disease↗

PubMed1999

Reduced C-terminal Src kinase (Csk) activities in hepatocellular carcinoma.

The proto-oncogene product pp60(c-src) is the cellular homologue of the Rous sarcoma transforming gene, and it is a non-receptor-linked and membrane-associated tyrosine kinase. There is a close correlation between elevated pp60(c-src) activity and cell transformation. We have recently reported that pp60(c-src) was activated in hepatocellular carcinoma (HCC) of human and Long-Evans cinnamon (LEC) rats. However, the mechanisms involved in this process remain unknown. C-terminal Src kinase (Csk) is a novel cytoplasmic protein tyrosine kinase that inactivates the members of the Src family protein tyrosine kinase in vitro. We investigated the role of Csk in hepatocarcinogenesis by analyzing the location, amount of Csk, and its kinase activity levels in nontumorous cirrhotic and tumorous sections of HCC of patients and an animal model of LEC rats. Csk tyrosine kinase activity was significantly reduced in tumorous tissues compared with nontumorous sections of patients as well as LEC rats. A single immunoreactive band at 50 kd was detected with Csk antibody in normal liver (NL), chronic hepatitis (CH), and nontumorous cirrhotic (NTC) segments of HCC of patients and LEC rats. In human tumorous tissues, Western blot revealed a 53-kd immunoreactive band, which was slightly larger than the usual 50-kd band of Csk. These results suggest that the reduced activity of tyrosine kinase of Csk may play an important role in the malignant transformation of hepatocytes in human and LEC rat, and the appearance of 53-kd Csk-related protein may be closely involved in the progression of cirrhosis to HCC in humans, and that 50-kd Csk may act as an antioncogene through the negative regulation of pp60(c-src) in the development of human HCC.

Aged↗

PubMed1999

MR imaging of hepatic injury in the LEC rat under a high magnetic field (7.05 T).

Visualization of copper-induced hepatitis (CuH) in LEC rats was performed by using an MRI apparatus equipped with a magnet producing a high magnetic field of 7.05 T. When three groups of LEC rats (6-16 [pre-hepatitis], 15-26 [acute hepatitis] and 40-77 [chronic hepatitis] weeks old) were examined by MRI under T2-weighted imaging conditions which are suitable for the diagnosis of human hepatitis, hypointense MR images of the livers were, as a whole, obtained in all groups, suggesting that these conditions were not adequate for imaging of CuH of LEC rats. The shortening of the T1 and T2 relaxation times of livers due to an excess amount of paramagnetic irons under the high magnetic field was responsible for the lowering of MR signal intensities of the livers, especially those of 15 to 26-week old rats showing acute hepatitis. However, theoretical calculation of the MR signal intensities using the T1 and T2 relaxation times of the livers indicated that their imaging might be possible under proton density-weighted conditions even with a high magnetic field. Experimental results showed that hepatic injury was visualized as hyperintense regions in the MR image of the liver in the acute-phase rat.

Animals↗

PubMed2000

Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats.

Copper (Cu) accumulating in a form bound to metallothionein (MT) in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease, was removed with ammonium tetrathiomolybdate (TTM), and the fate of the Cu complexed with TTM and mobilized from the liver was determined. TTM was injected intravenously as a single dose of 2, 10 or 50 mg TTM/kg body weight into LEC and Wistar (normal Cu metabolism) rats, and then the concentrations of Cu and molybdenum (Mo) in the bile and plasma were monitored with time after the injection. In Wistar rats, most of the Mo was excreted into the urine, only a small quantity being excreted into the bile, while Cu excreted into the urine decreased. However, in LEC rats, Cu and Mo were excreted into the bile and blood, and the bile is recognized for the first time as the major route of excretion. The Cu excreted into both the bile and plasma was accompanied by an equimolar amount of Mo. The relative ratio of the amounts of Cu excreted into the bile and plasma was 40/60 for the low and high dose groups, and 70/30 for the medium dose group. The systemic dispositions of the Cu mobilized from the liver and the Mo complexed with the Cu were also determined for the kidneys, spleen and brain together with their urinal excretion. Although Mo in the three organs and Cu in the kidneys and spleen were increased or showed a tendency to increase, Cu in the brain was not increased at all doses of TTM.

Animals↗

PubMed2005

A novel H28Y mutation in LEC rats leads to decreased NAT protein stability in vivo and in vitro.

Nocturnal melatonin production is reportedly controlled by the rhythms of serotonin N-acetyltransferase (NAT, or arylalkylamine N-acetyltransferase). While analyzing the melatonin synthetic pathways of Long Evans cinnamon (LEC) rats mutant for PINA, a pineal night-specific ATPase defective in Wilson disease, we discovered that NAT activity and protein levels are greatly reduced in LEC rats, and that the highly conserved histidine 28 is mutated to tyrosine. To study the effect of H28Y, we isolated a new strain of rat termed LPN that is mutant for NAT but wildtype for both PINA and coat color. Compared with control rats, the LPN rats displayed low NAT protein levels and enzyme activities. These results suggest that the H28Y mutation in NAT is the cause of reduced NAT levels in vivo. The identical H28Y mutation was also found in Sprague-Dawley rats from Zivic-Miller, suggesting it may be a common mutation in rodents. When analyzed in bacterial cells and HEK293 cells, the mutation resulted in reduction of both NAT protein stability and catalytic activity, confirming that the in vivo NAT phenotype in LPN rats was due to the H28Y mutation. Further analysis of the NAT-H28Y will focus on the mechanisms of the increased degradation both in vitro and in vivo, which will facilitate our understanding of how melatonin synthesis is controlled at the molecular level.

Adenosine Triphosphatases↗

PubMed2004

Restoration of copper metabolism and rescue of hepatic abnormalities in LEC rats, an animal model of Wilson disease, by expression of human ATP7B gene.

Hepatic abnormalities in Long-Evans Cinnamon (LEC) rats, an animal model of Wilson disease (WD), were restored by the expression of the human ATP7B cDNA under the control of CAG promoter. Expression of ATP7B transcript and protein in the liver of the transgenic rats resulted in the restoration of biosynthesis of holoceruloplasmin and biliary copper excretion. Meanwhile, transgenic rats showed striking improvements in their hepatic abnormalities, i.e., rescue from fulminant hepatitis, late onset of hepatic cholangiofibrosis, suppression of hepatocellular carcinoma and much improved survival rates. Moreover, dramatic decreases were noted both in the levels of hepatic copper and iron in transgenic rats before the occurrence of hepatitis. These results indicated that the human ATP7B product compensated for the deficiency of the endogenous rattus protein and did function in intrahepatic copper transport by secreting copper into the plasma via incorporation into ceruloplasmin and by the excretion of copper into the bile, and that ATP7B is critical to hepatic dysfunctions in WD. This first successful transgenic rescue has important implications for the gene therapy of WD.

Adenosine Triphosphatases↗

PubMed2001

New rat model for attention deficit hyperactive disorder (ADHD).

PURPOSE: In a strain of the Long-Evans Cinnamon (LEC) rats, we found spontaneously hyperactive animals designated as "wiggling," and established a congenic wiggling (Wig) rat by transferring the gene from the LEC to the Wistar King-Aptekman/Hokkaido (WKAH) strain. We evaluated the feasibility of the Wig rat for an animal model of human attention deficit hyperactive disorder (ADHD). METHODS: Mode of inheritance was examined by use of linkage analyses. Motor activity, behavior, and working memory were assessed by use of electric digital counters, open field test, and Y-maze and water-maze tests. RESULTS: The abnormal behavior, including hyperactivity, was transmitted in autosomal recessive mode. Diurnal and nocturnal motor activity of 12- to 14-week-old Wig rats was markedly higher than that of controls, and this hyperactivity was more prominent during nighttime than daytime. Ambulation in the open-field test was significantly increased in Wig rats, but rearing was decreased in Wig rats, compared with controls. Results of the Y-maze tests indicated that spontaneous alternation behavior was significantly impaired in Wig rats, although there was no difference in the total arm entries. The water-maze test could not be performed because, when exposed to water, Wig rats panicked and almost drowned. CONCLUSIONS: Wig rats are hyperactive and have impaired working memory and impulsive behavior, as assessed by the motor activity and open-field tests and the Y-maze test, and these abnormalities are transmitted by a single gene with Mendelian pattern. Wig rats represent an excellent animal model of human ADHD.

Animals↗

PubMed2000

A possible novel src-related tyrosine kinase in cancer cells of LEC rats that develop hepatocellular carcinoma.

BACKGROUNDS/AIMS: Src-related protein tyrosine kinase is known to be related to cell transformation. In this study, we report a possible novel src-related tyrosine kinase of 100 kDa specifically expressed in the nuclei of hepatocytes and/or cancer cells in Long-Evans Cinnamon rats, one of the experimental models of hepatocellular carcinoma. METHODS: Src-related protein tyrosine kinase in hepatocytes of Long-Evans Cinnamon rats was analyzed by using immunohistochemistry and Western blot and in vitro tyrosine kinase assay using a specific antibody (src antibody) against a synthetic peptide corresponding to the conserved autophosphorylation site of src family tyrosine kinases. RESULTS: Src-related protein was found to be expressed in the nuclei of hepatocytes and/or cancer cells in Long-Evans Cinnamon rat liver, exhibiting tyrosine kinase activity, and migrated to the position of 100 kDa. The protein quantity and activity of this 100-kDa src-related protein tyrosine kinase significantly increased with the progress of chronic hepatitis to hepatocellular carcinoma, especially in the tumorous portion of the liver. On the other hand, the 100-kDa src-protein tyrosine kinase was not observed in the nuclei of hepatocytes and/or cancer cells in normal age-matched control Wistar rats. CONCLUSIONS: Since the src-family tyrosine kinases have been observed at a molecular weight of 55 to 62 kDa and located in the hepatocellular membrane and/or cytoplasm, the 100-kDa src-related protein tyrosine kinase observed in the present study may be novel, and closely related to the pre-cancerous and cancerous process in Long-Evans Cinnamon rat liver.

Animals↗