Abnormal intracellular distribution of O6-alkylguanine-DNA-alkyltransferase in hepatitis B cirrhotic human liver: a potential cofactor in the development of hepatocellular carcinoma.

Abstract

The expression of O6-alkylguanine-DNA-alkyltransferase (ATase), which is responsible for repair of the promutagenic and cytotoxic DNA lesion O6-alkylguanine, was examined by immunostaining in a series of liver sections from normal and hepatitis-B cirrhosis patients using a polyclonal anti-human ATase antiserum. In 10 normal liver sections, the ATase staining was predominantly nuclear and very intense in the majority of the hepatocytes with a panacinar distribution. In contrast, in 15 hepatitis-B sections, the ATase was located mainly in the cytoplasm of the majority of the hepatocytes and had a perinuclear distribution. Scattered hepatocytes showed a more intense staining involving all or part of their cytoplasm; nuclear staining, however, was reduced in intensity, being inconspicuous in seven and patchy and weak in eight. ATase activity in extracts of 10 of the hepatitis-B livers varied from approximately 90 to 360 fmoles/mg protein and there was no apparent relationship between these levels and the cellular distribution of the enzyme. The sequestration of the ATase protein in the cytoplasm, away from its site of action in the cell nucleus suggests that in hepatitis-B cirrhosis, the repair of O6-alkylguanine lesions by ATase may be less efficient than in normal hepatocytes. The abnormal cellular distribution of ATase may thus be an additional cofactor in the development of hepatitis-B-associated hepatocellular carcinoma.