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The Rate of Incorporation of Labeled Thymidine into the Deoxyribonucleic Acid of Regenerating Rat Liver in Relation to the Amount of Liver Excised^*

( The John Collins Warren Laboratories of the Huntington Memorial Hospital of Harvard University at the Massachusetts General Hospital, Boston, Massachussetts)

The rate of incorporation of thymidine-2-C¹⁴ into DNA was determined at intervals during the first 2 days of hepatic regeneration following excision of varying amounts of liver in weanling, young adult, and older rats.

In young adults, extirpation of 9 or 34 per cent of the liver resulted in small increases in the respective 2-hour rates of DNA labeling to relatively constant levels, or "plateaus," over the 20- to 48-hour postoperative period. Removal of 43 or 68 per cent caused sharp bursts, or "peaks," in respective rates of labeling at 18–30 hours, followed by decreases to plateaus which persisted until 48 hours or more. The logarithms of the plateau rates of DNA labeling were directly proportional to the per cent of liver removed over the entire range of hepatic deficiency. The logarithms of the peak rates were similarly proportional—i.e., although the absolute rates of incorporation were increased, the percentage increments between these points were approximately the same as for the plateau rates.

In weanling and older rats peaks of DNA labeling occurred after removal of only 9 per cent of the liver, and the logarithms of the peak rates were proportional to the amounts of liver excised over the entire 9–68 per cent range, with percentile increments approximately the same as above. The plateau rates, estimated from 68 per cent liver removal only, exhibited a somewhat similar trend.

In radioautographs prepared from livers exposed to thymidine-H³ throughout the 18- to 40-hour postoperative period (hence, including the peak plus transition to plateau) labeled nuclei appeared first at the periphery of hepatic lobules, especially when the deficiency was acute, whereas they were randomly scattered during normal growth. Smears of isolated nuclei supported the short-term data in showing a pronounced elevation in per cent of labeled nuclei in animals with 43–68 per cent removals compared with those with only 9–34 per cent.

Thus, in 1- to 15-month-old rats the rate of DNA labeling increases logarithmically in direct proportion to the amount of liver excised at the peak period (also, in young adults at least, at the plateau), the percentage increments in rate being approximately the same for all, except that, if the liver loss exceeds a certain critical amount, which differs with age, some additional mechanism comes into play, raising the baseline and resulting in higher levels of labeled thymidine incorporation.

^* This is publication No. 1174 of the Cancer Commission of Harvard University. An earlier report of these findings was presented at meetings of the Federation of American Societies for Experimental Biology (4).

The work was supported by grants CA 02146-11 of the U.S. P.H.S. and E-50A of the American Cancer Society.

Received 4/25/64.

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