Cell type-specific induction of O-6-alkylguanine-DNA alkyltransferase mRNAexpression in rat liver during regeneration, inflammation and preneoplasia

Purpose and Methods: To investigate the potential role of an aberrant cellu lar DNA repair in target cells during malignant transformation we studied c ell type-specific mRNA expression of the DNA repair protein O-6-alkylguanin e-DNA alkyltransferase (O-6-AGT) in normal and regenerating rat liver, chro nic hepatitis and preneoplastic liver lesions by in situ hybridization and semiautomatic image analysis. Results: O-6-AGT mRNA expression was found to be four to five times higher in hepatocytes than in nonparenchymal cells. A 1.9-fold increase in O-6-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. Ethylnitr osourea produced an enhancement of mRNA levels up to 1.6-fold in hepatocyte s without regional differences. In megalocytic hepatocytes of Long-Evans Ci nnamon rats with chronic hepatitis, a 4.4-fold mRNA induction was found. In small preneoplastic lesions induced after chronic diethylnitrosamine-expos ure, O-6-AGT mRNA expression was identical to that of adjacent normal tissu e. Intermediate and large lesions revealed 1.5- to 1.6-fold higher mRNA lev els. Conclusions: These results suggest an induction of O-6-AGT mRNA expres sion in hepatocellular target tissue under conditions of increased carcinog en sensitivity. The O-6-AGT expression in early preneoplastic lesions did n ot differ from normal surrounding liver tissue, thus excluding the possibil ity that progression of preneoplasia in rat liver is associated with a defi cient mRNA expression of this DNA repair protein. On the contrary, enhanced O-6-AGT mRNA expression in more advanced foci and early neoplastic nodules may confer a selective advantage upon early malignant hepatocytes with reg ard to further tumor progression.