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Two-Stage Control of Cell Proliferation Induced in Rat Liver by -Hexachlorocyclohexane¹

Institut für Toxikologie und Pharmakologie der Philipps-Universität Marburg a.d. Lahn, 355 Marburg a. d. Lahn, Germany

Determinants of the timing of DNA synthesis in rat liver were studied, using -hexachlorocyclohexane as a tool for stimulation of cell proliferation. One determinant is the time of -hexachlorocyclohexane administration. The increase in DNA synthesis starts after a lag phase (prereplicative phase) of minimally 20 hr. Use of animals adapted to a controlled feeding and lighting schedule revealed a second determinant provided by food consumption. Initiation of DNA synthesis is suppressed by fasting or protein deprivation and occurs 5 to 8 hr after readministration of a protein-containing diet. The light-dark rhythm has no direct influence on the timing of DNA synthesis. Stimulation of hepatic DNA synthesis, therefore, appears to require two different sequential signals. The first is provided by -hexachlorocyclohexane, and the second is provided by protein intake. In the absence of the second signal, committed cells are arrested at a critical point of the prereplicative phase and accumulate. Protein intake permits release from the block, and the accumulated cells enter the S period almost synchronously after completion of the remaining 5 to 8 hr of the prereplicative phase. These observations provide a means of synchronizing, in the living animal, a proliferating population of hepatocytes. In addition, they offer an explanation for the diurnal rhythmicity in the rate of hepatic cell proliferation.

¹ This study was supported by Deutsche Forschungsgemeinschaft.

Received 6/ 8/76. Accepted 10/11/76.

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