The effect of two periods of short-term fasting during the promotion stage of hepatocarcinogenesis in rats: the role of apoptosis and cell proliferation

H Hikita
1997 Carcinogenesis  
these effects are not entirely clear but may involve changes in School, glucose utilization (14), the basic metabolic rate (15, 16) , 1 To whom correspondence should be addressed hormonal levels (17, 18) , and oxidant processes in the organism The loss of body and liver weight caused by chronic (19,20). In contrast, fasting or complete caloric restriction caloric restriction and its effects on carcinogenesis are well causes a dramatic shift in the organism's metabolism to known; however, the
more » ... wn; however, the effects of acute fasting on carcinogengluconeogenesis and lipolysis (21) , hepatic autophagy (22) esis have not been intensively investigated. We have studied and a dramatic loss in glutathione (23). some parameters of rat liver during short-term fasting and Recently, Pani and colleagues (24,25) have studied the effect its effect on the stage of promotion in hepatoof acute fasting followed by refeeding on hepatocarcinogenesis carcinogenesis in rats. During two fasting periods, body and using two different protocols. Their studies indicated that acute liver weight decreased remarkably. Bromodeoxyuridine fasting followed by refeeding induced a positive effect on the (BrdU) labeling indices (LI) decreased, and cell density growth of altered hepatic foci (AHF*) in contrast to chronic increased prominently in liver sections. Hematoxylin and caloric restriction, which caused an inhibition of growth of eosin-stained and nick end labeling (TUNEL)-stained sec-AHF or even their disappearance. In light of previous studies tions showed an increase of apoptotic bodies in the absence in our laboratory on the loss and regrowth of AHF on removal of necrosis during the fasting period. Moreover, gel electroof the promoting agent with subsequent readministration of phoresis of DNA isolated from whole liver revealed ladder the agent (27) , we studied the effect of combining acute fasting formation indicative of nucleosomal DNA cleavage. At the and removal of the promoting agent with subsequent refeeding beginning of the fasting period livers exhibited a small but and readministration of the promoting agent on quantitative definite number of altered hepatic foci (AHF) expressing stereologic parameters of AHF as well as the replication and glutathione S-transferase, placental form (GST-P), but at apoptosis of cells within such lesions. the end of the fasting period no AHF were discernible in Materials and methods all livers of animals subjected to the fasting period. After Animals and treatment refeeding, cell density and the incidence of apoptotic bodies Female SpragueϪDawley rats (Harlan SpragueϪDawley Co., Madison, WI) decreased prior to a transient increase of BrdU LI. The were divided into four groups (groups AϪD). Rats were housed, 2 or 3 in percentage volume of liver occupied by AHF of fasted rats each cage, and were given water ad libitum. Rats were subjected to a 70% was significantly greater than that of control rats at 140 partial hepatectomy (PH) at 150 Ϯ 10 g body wt and were administered days after initiation. These results suggest that both the 10 mg/kg body wt diethylnitrosamine (DEN; Eastman Kodak, Rochester, MO) dissolved in tricaprylin (Sigma, St Louis, MO) by stomach tube 24 h after liver weight loss and the complete loss of discernible AHF PH, as initiation. from short-term fasting was caused by (i) decrease of cell The dietary groups are summarized in Figure 1. On the first day all rats volume, (ii) cell loss by apoptosis, and (iii) a decrease were fed a laboratory chow diet (Teklad Crude, containing 24% protein). of hepatocyte proliferation. Furthermore, this relatively Group A was fed this diet containing 0.05% phenobarbital (PB) ad libitum transient liver weight loss enhanced the promotion of from day 2 throughout the experimental period. Groups B, C and D were fasted from day 16 to day 28 except for day 21 to day 23, as indicated in hepatocarcinogenesis, possibly by enhanced cell prolifera-Figure 1. The two days of ad libitum feeding (days 21 and 22) were inserted tion compensatory to the fasting cycles. in order to allow a maximal fasting experience with minimal fatalities. During days 21 and 22, days in which the animals were fed, groups B and D received a 60% and 6% protein-containing diet respectively. Group C was fed the 24% protein diet with 0.05% PB on days 21 and 22 between the two 5-day fasting
doi:10.1093/carcin/18.1.159 pmid:9054602 fatcat:cyqjdnfv25ai7hzv32gpyxhjva