Cell type-specific induction of O6-alkylguanine-DNA alkyltransferase mRNA expression in rat liver during regeneration, inflammation and preneoplasia.

PURPOSE AND METHODS

To investigate the potential role of an aberrant cellular DNA repair in target cells during malignant transformation we studied cell type-specific mRNA expression of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (O6-AGT) in normal and regenerating rat liver, chronic hepatitis and preneoplastic liver lesions by in situ hybridization and semiautomatic image analysis.

RESULTS

O6-AGT mRNA expression was found to be four to five times higher in hepatocytes than in nonparenchymal cells. A 1.9-fold increase in O6-AGT mRNA was observed after partial hepatectomy. Intraperitoneal injection of diethylnitrosamine led to a 1.3-fold and 2.6-fold rise in periportal and perivenous hepatocytes, respectively. Ethylnitrosourea produced an enhancement of mRNA levels up to 1.6-fold in hepatocytes without regional differences. In megalocytic hepatocytes of Long-Evans Cinnamon rats with chronic hepatitis, a 4.4-fold mRNA induction was found. In small preneoplastic lesions induced after chronic diethylnitrosamine-exposure, O6-AGT mRNA expression was identical to that of adjacent normal tissue. Intermediate and large lesions revealed 1.5- to 1.6-fold higher mRNA levels.

CONCLUSIONS

These results suggest an induction of O6-AGT mRNA expression in hepatocellular target tissue under conditions of increased carcinogen sensitivity . The O6-AGT expression in early preneoplastic lesions did not differ from normal surrounding liver tissue, thus excluding the possibility that progression of preneoplasia in rat liver is associated with a deficient mRNA expression of this DNA repair protein. On the contrary, enhanced O6-AGT mRNA expression in more advanced foci and early neoplastic nodules may confer a selective advantage upon early malignant hepatocytes with regard to further tumor progression.