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Immunohistochemical localization of endothelin-1/big endothelin-1 in normal liver, liver cirrhosis and hepatocellular carcinoma.

In order to clarify the characteristics of cellular localization of ET-1/big ET-1 in liver tissues, we carried out immunohistochemical study on 30 normal, 87 cirrhosis (LC) and 55 hepatocellular carcinoma (HCC) liver specimens using anti-ET-1 antibody and anti-big ET-1 antibody and further performed in situ hybridization on 5 LC liver specimens. Positive immunostaining of hepatocytes of normal and LC livers, and tumor cells of HCC was obtained. The frequency of positive cells for ET-1 and big ET-1 of normal liver was very low. In contrast, LC hepatocytes were stained much more frequently for both ET-1 and big ET-1 than those of normal liver (P < 0.01). In the HCC livers hepatoma cells showed intermediate frequency of positive cells between normal and LC livers. Big ET-1, not ET-1, expression in HCC was significantly high compared with that of normal liver (P < 0.01). Specific signals for ET-mRNA were not detected in hepatocytes of LCs by in situ hybridization. ETs detected in hepatocytes by immunohistochemistry, therefore, seem not to have been synthesized locally. The origin of ETs is not clear but they might have been taken up from the circulation through ET receptors on hepatocytes. Although the clearance mechanism of ETs by ET-converting enzyme or other peptidases in liver has not been elucidated, the mechanisms seem to be absent or impaired in LC and/or HCC liver since the frequency and intensity of ET-positivity in the diseased hepatocytes are significantly high than those of normal liver. In addition, a disturbance of ET excretion into the bile may be also responsible for the ET storage. Elevation of serum ET levels in LC may be caused by disturbance of ET degradation and/or leakage of bile into the blood, as the ET is excreted through the biliary system.