Cell cycle-dependent initiation of adenosine triphosphatase-deficient populations in adult rat liver by a single dose of N-methyl-N-nitrosourea.
Changes in the sensitivity of hepatocytes to initiation during the cell cycle were investigated in partially resected hydroxyurea-synchronized regenerating rat liver. At defined periods of the cell cycle the animals were given injections of a single dose of N-methyl-N-nitrosourea (MNU) (25 mg/kg) and were subsequently exposed to diethylnitrosamine for 30 days (2 mg/kg/day) or to phenobarbital (0.05% in the diet) for 80 days. Adenosine triphosphatase-deficient cell populations in the liver, determined 90 days after MNU treatment, served as a marker for the initiating action of the carcinogen. Few foci were observed when MNU treatment was performed during early G1. Their frequency increased steeply after MNU injection at G1-S boundary and reached a maximum after carcinogen exposure in early S phase, when the number of adenosine triphosphatase-deficient foci was higher by a factor of 5 (after diethylnitrosamine feeding) or 10 (after phenobarbital feeding) than after MNU exposure in early G1 phase. A rapid decline was observed in middle S phase. The frequency of altered foci after MNU in late S phase and during G2-M was in the same range as in early G1. Their size distribution was similar in all groups. The results confirm and extend earlier observations of an increased initiating effect of a carcinogen during liver regeneration. Under in vivo conditions, hepatocytes are, after HU synchronization, at the highest risk of being initiated by a carcinogen when they traverse the early S phase of the cell cycle.
Rabes
H M
HM
Müller
L
L
Hartmann
A
A
Kerler
R
R
Schuster
C
C
D000251:Adenosine Triphosphatases / Q000172:deficiency*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004334:Drug Administration Schedule; D006498:Hepatectomy; D008099:Liver / Q000166:cytology* / Q000201:enzymology; D008297:Male; D008770:Methylnitrosourea / Q000008:administration & dosage*; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology*; D051381:Rats
D008770:Methylnitrosourea; D004247:DNA; D000251:Adenosine Triphosphatases