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Cell Loss and Proliferation Induced by N-2-Fluorenylacetamide in the Rat Liver in Relation to Hepatoma Induction¹

Institute of Environmental Medicine, New York University Medical Center, New York, New York 10016

Cell loss and replacement were examined in relation to tumor induction following various doses and exposure patterns of the carcinogen N-2-fluorenylacetamide (2-FAA) in the diet of male albino rats. In Experiment 1, the hepatic DNA was prelabeled by the injection of thymidine-³H (TdR-³H) into weanling animals, and the loss of the tritium activity was measured at various times after the start of the carcinogen treatment. In Experiment 2, single injections of TdR-³H were given at various times during continuous exposure to the carcinogen at levels of 0.03, 0.01, and 0.003%. The uptake of TdR-³H in hepatic DNA, the parenchymal cell-labeling index, and the total hepatic DNA were determined. In Experiment 3, the incidence of hepatic carcinoma was determined for various exposure durations to 0.03, 0.01, 0.003, and 0.001% 2-FAA. At 42 days after the start of administration of 0.03% 2-FAA, the uptake of TdR-³H in the hepatic DNA increased markedly. With 0.03% 2-FAA, the pulse labeling index increased progressively between 42 and 120 days, while the pulse labeling index for 0.01% 2-FAA showed no increase until 120 days. With 0.03% 2-FAA, the prelabeled DNA decreased markedly between 42 and 72 days, while the total hepatic DNA increased by about 15 to 20% by 72 days. The tumor data showed that a 365-day exposure to 0.01% 2-FAA was approximately equivalent to a 112-day exposure to 0.03% 2-FAA, i.e., an equivalent tumor yield for equal total doses. However, 28- and 56-day exposures to 0.03% 2-FAA were far less effective than 112-day exposures to 0.01% 2-FAA. The data suggest that, at 0.03%, the carcinogen produced an increase in the parenchymal cell replication rate that correlated with the tumor incidence and that, when the carcinogen was stopped early enough to prevent tumors, very little of the original DNA was lost and the replication rate of the parenchymal cells was only slightly increased.

¹ This investigation was supported by Project Grant AT(11-1) 3380 from the United States Atomic Energy Commission and is part of a center program supported by the National Institute of Environmental Health Sciences, Grant ES 00260.

² Present address: Department of Medicine, North Carolina Memorial Hospital, Chapel Hill, N. C. 27514.

Received 12/22/71. Accepted 6/22/72.

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