Intralobular distribution of preneoplastic foci in rat liver after a single dose of N-methyl-N-nitrosourea (MNU) following partial hepatectomy.

ATPase-deficient foci in rat liver, considered to be clonal in origin and possible precursors of hepatocellular carcinomas, were induced by injecting male Wistar AF/Han (200-220 g) rats with N-methyl-N-nitrosourea (MNU) (25 mg/kg) 16 or 22 h after partial hepatectomy and feeding for 80 days with a diet containing phenobarbital. The animals were killed after 90 days and the intralobular distribution of the preneoplastic foci was analysed quantitatively. The locations of 48 foci in the 16-h group and 22 foci in the 22-h group were determined from serial sections and blocks of liver from five animals. The mean distance of the foci from the portal vein in the 16-h group (385 microns) was 30% less than the distance of randomly selected points (546 microns), while the mean distance of the foci in the 22-h group (450 microns) was 16% less than the random points (535 microns). The mean diameter of the foci (235 microns) was 17% greater in the 22-h group than in the 16-h group (196 microns). We suggest that the cells in early S phase which are periportally situated 16 h after partial hepatectomy and occupy an intermediary position at 22 h represent the sensitive target population for initiation.