Transformation sensitivity in early S-phase and clonogenic potential are target-cell characteristics in liver carcinogenesis by N-methyl-N-nitrosourea

Changes in the transformation sensitivity of hepatocytes during the cell cycle were in relation to clonogenicity investigated in partially resected rat liver. The hourly rate of the G1-S transit was measured in a control group by means of tritium-labelled thymidine (3H-TdR). At defined periods after partial hepatectomy the animals were injected with a single dose of N-methyl-N-nitrosourea (MNU) (25 mg/kg) and subsequently exposed to phenobarbital (0.05% in the diet) for 80 days. ATPase-deficient cell populations which arise by clonal growth (Rabes et al., 1982) were determined in the liver 90 days after MNU treatment and served as a marker for the initiating action of the carcinogen. The number of foci appeared to be related to the hourly rate of influx of hepatocytes into DNA synthesis at the time of MNU administration. Few foci were observed after MNU exposure in G1 and their frequency increased steeply when MNU treatment coincided with the first peak of cellular G1-S transit. As the rate of influx into S-phase decreased, so did the number of foci, despite the proportion of cells in S-phase still being at a maximum. The possibility of a gradient of clonogenicity existing within the cells of the liver lobule is envisaged. It is suggested that proliferative cells of the peri-portal region, which begin DNA synthesis early after partial hepatectomy, have the greatest ability to form clones of ATPase-deficient putative pre-neoplastic foci after initiation by a carcinogen and might thus represent, if exposed to carcinogen in early S-phase, the effective target cell population for the induction of hepatocellular carcinomas.