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Cell Cycle-dependent Initiation of Adenosine Triphosphatase-deficient Populations in Adult Rat Liver by a Single Dose of N-Methyl-N-nitrosourea¹

Institute of Pathology, University of Munich, Thalkirchner Str. 36, D-8000 Munich 2, Federal Republic of Germany

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.

¹ Supported by grants from Deutsche Forschungsgemeinschaft and Deutsche Stiftung für Krebsforschung, Dr. Mildred Scheel-Stiftung.

² To whom requests for reprints should be addressed.

³ Present address: Departamento de Patologia da Fundacao Faculdade Federal de Ciências Médicas, Porto Alegre, Brasilia.

Received 1/29/85. Revised 5/17/85. Revised 7/24/85. Revised 9/18/85. Accepted 10/16/85.

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