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Search for Endogenous Liver Colony-forming Units in F344 Rats Given a Two-Thirds Hepatectomy during Short-Term Feeding of 2-Acetylaminofluorene¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706

To search for endogenous liver colony-forming units in livers of male F344 rats, three cell selection regimens were used. Rats were given a two-thirds hepatectomy (PH) on Day 7 of a 14-day dietary administration of the hepatocarcinogen 2-acetylaminofluorene (AAF), given at a concentration of 0.02, 0.04, or 0.06% (AAF-PH regimens). Rats were sacrificed at intervals up to Day 21. Although extensive liver cell proliferation was induced by the AAF-PH regimens, a total of only four endogenous liver colony-forming units were detected in standard liver sections prepared from 46 AAF-PH-treated rats; the liver colony-forming units appeared in two rats sampled on Day 21.

Liver cell hyperplasia was induced by the AAF-PH regimens and was reflected by an increase in the liver weight/body weight ratio, an increase in standard liver section area, and an increase in specific activity of [³H]DNA extracted from the livers of rats receiving [³H]thymidine during the AAF-PH regimen. The characteristic peak of DNA synthesis, observed at 24 hr post-PH in the livers of control rats, was absent in AAF-PH-treated rats, but DNA-specific activity began to increase at three days post-PH, peaked at seven to ten days post-PH, and was greater with higher concentrations of AAF. The acinar distribution of liver cells proliferating during the AAF-PH regimen was evaluated in standard liver sections by microscopic determinations of cell densities and autoradiographic determinations of nuclear incorporation of [³H]thymidine as an estimate of the DNA synthesis index. At Day 14, the AAF-PH regimens induced approximately three-fold greater cell densities, compared with controls, and a DNA synthesis index in the range of 15 to 45% within 85 µm of the terminal portal venule in Zone 1 of Rappaport, with a gradual decrease to control levels at about 255 µm from the terminal portal venule. Morphologically, most of the proliferating cells in Zone 1 resembled bile duct epithelial cells with a few intervening cells resembling oval cells. The DNA synthesis index, observed in two other morphologically distinguishable cell types, increased with higher AAF concentrations. One cell type exhibited small, pleiomorphic nuclei, distributed evenly in Zones 2 and 3; the other exhibited larger, rounded nuclei located predominantly in Zone 3.

AAF-PH regimens containing higher concentrations of AAF adversely affected survival. At Day 14, the percentages of survival of rats fed diets supplemented with 0.02, 0.04, or 0.06% AAF were, respectively, 100, 89, and 65%. Reductions in body weights, thymus weight/body weight ratios, and liver weight/body weight ratios paralleled decreased survival.

By Day 21, all AAF-PH-treated rats fed diets supplemented with 0.02, 0.04, or 0.06% AAF consumed, respectively, 85, 62, or 56% of the amount of diet consumed by rats fed control diet only; the total amounts of AAF ingested were 19, 34, and 40 mg/rat, respectively. The pattern of daily intake of 0.02% AAF diet revealed a substantial decrease in diet consumption for two days post-PH.

¹ This investigation was supported by Grants CA-07175 and CA-24818 awarded by the National Cancer Institute, Department of Health, Education, and Welfare.

² Research Scholar of the Foundation for Cancer Research, Chicago.

Received 9/29/80. Accepted 1/30/81.