THE EFFECT OF 2 PERIODS OF SHORT-TERM FASTING DURING THE PROMOTION STAGE OF HEPATOCARCINOGENESIS IN RATS - THE ROLE OF APOPTOSIS AND CELL-PROLIFERATION

The loss of body and liver weight caused by chronic caloric restrictio n and its effects on carcinogenesis are well known; however, the effec ts of acute fasting on carcinogenesis have not been intensively invest igated, We have studied some parameters of rat liver during short-term fasting and its effect on the stage of promotion in hepatocarcinogene sis in rats. During two fasting periods, body and liver weight decreas ed remarkably, Bromodeoxyuridine (BrdU) labeling indices (LI) decrease d, and cell density increased prominently in liver sections, Hematoxyl in and eosin-stained and nick end labeling (TUNEL)-stained sections sh owed an increase of apoptotic bodies in the absence of necrosis during the fasting period, Moreover, gel electrophoresis of DNA isolated fro m whole liver revealed ladder formation indicative of nucleosomal DNA cleavage, At the beginning of the fasting period livers exhibited a sm all but definite number of altered hepatic foci (AHF) expressing gluta thione S-transferase, placental form (GST-P), but at the end of the fa sting period no AHF were discernible in all livers of animals subjecte d to the fasting period, After refeeding, cell density and the inciden ce of apoptotic bodies decreased prior to a transient increase of BrdU LI, The percentage volume of liver occupied by AHF of fasted rats was significantly greater than that of control rats at 140 days after ini tiation, These results suggest that both the liver weight loss and the complete loss of discernible AHF from short-term fasting was caused b y (i) decrease of cell volume, (ii) cell loss by apoptosis, and (iii) a decrease of hepatocyte proliferation, Furthermore, this relatively t ransient liver weight loss enhanced the promotion of hepatocarcinogene sis, possibly by enhanced cell proliferation compensatory to the fasti ng cycles.