Hepatocyte sensitivity to initiation of
carcinogenesis was studied as a function of the cell cycle phase in which damage was incurred. Hepatocytes were stimulated to proliferate by a two-thirds partial hepatic resection, and their proliferation was synchronized further by postsurgical treatment with
hydrocortisone. Groups of male F344 rats were given a single administration of
methyl(acetoxymethyl)nitrosamine, a highly reactive methylating agent, at various times after two-thirds partial hepatic resection when hepatocytes were in defined phases of the cell cycle. Beginning 3 wk after the treatment and for 37 wk thereafter, rats were fed a diet containing 0.05%
phenobarbital to promote the expression of initiated hepatocytes. At 45 wk
after treatment with
carcinogen hepatocytic
neoplasms were enumerated. The greatest yield of
neoplasms (5.4 per liver) was observed in the group treated 16 h after two-thirds partial hepatic resection or at the time when proliferating hepatocytes began to enter the S phase of the cell cycle. The least yield of
neoplasms (0.8 per liver) was identified in the group treated with
methyl(acetoxymethyl)nitrosamine when hepatocytes were early in G1. In the proliferating hepatocytes sensitivity rose continuously during G1 to a peak at the G1-S border and then fell continuously as hepatocytes traversed S, G2, and M. This pattern of response could not be attributed to variation in hepatic
esterase which activates
methyl(acetoxymethyl)nitrosamine or to variation in methylation of
DNA. The results support a model in which
carcinogen-induced genetic alterations, occurring at the time of or soon after damaged cells enter the S phase, represent irreversible events that contribute to the initiation of
carcinogenesis.