Effects of a Choline‐deficient Diet and a Hypolipidemic Agent on Single Glutathione S‐Transferase Placental Form‐positive Hepatocytes in Rat Liver

Abstract

Using the placental form of glutathione S-transferase (GST-P) as a marker of carcinogen-initiated hepatocytes, we investigated how a choline-deficient (CD) diet and BR931, a carcinogenic hypolipidemic agent, modify populations of single GST-P-positive hepatocytes. The liver of male Fischer rats (6-7 weeks old) fed a CS or basal diet contained mostly single or double GST-P-positive hepatocytes. Feeding a CD diet for 2-4 weeks led to increases in the number of aggregates of two and three GST-P-positive hepatocytes. By 8-12 weeks, there was an emergence of discrete foci of GST-P-positive hepatocytes consisting of more than 20 hepatocytes. Feeding a BR931 diet for 4-8 weeks resulted in no significant change in the number of single GST-P-positive hepatocytes in the liver as compared to feeding a basal diet. It is suggested that single GST-P-positive hepatocytes in the liver of relatively young rats maintained on a commercial diet may represent endogenously initiated cells. A CD diet promotes endogenously initiated cells to form larger aggregates or foci of GST-P-positive cells.

Inhibitory effect of dietary iron deficiency on inductions of putative preneoplastic lesions as well as 8-hydroxydeoxyguanosine in DNA and lipid peroxidation in the livers of rats caused by exposure to a choline-deficient L-amino acid defined diet

“…Despite the presence of a number of reports indicating an initiating ability of dietary choline (or methyl donors) deficiency (3,5,23,35,57), it has been argued that it does not initiate rat hepatocytes per se but only promotes pre-existing spontaneously (or endogenously) initiated hepatocytes (9,58). Our data would support, however, the initiating ability of the CDAA diet, dependent on the presence of sufficient iron.…”

Endogenous liver carcinogenesis in the rat *

“… 35,88 It is thus unlikely that dietary choline defiency only exerts a promoting activity on pre‐existing, ‘spontaneously initiated’ hepatocytes. 89,90 The fact of irreversible changes is indicated by the finding that preneoplastic lesions persist when rats are fed the CDAA diet for 24 weeks and then a control diet for 28 weeks. 29 It is necessary, however, to assess the initiating mechanisms caused by dietary choline deficiency in more detail.…”

Comparative Changes in the Liver of Female Fischer-344 Rats after Short-Term Feeding of a Semipurified or a Semisynthetic L-Amino Acid-Defined Choline-Deficient Diet

“…5), and the degrees induced by the CD diet in males (16), or by a severe lipotrope-deficient diet in females (29). Nonetheless, the BrdU-LIs show that the CDAA diet caused an enhanced and high degree of cell proliferation in females that increased steadily for 12 (28), there appears to be no consensus as yet about their nature and role in lipotrope-deficient diet models (9,14,16,31,35). The major uncertainties stem from the fact that in the latter, enzyme-altered hepatocytes develop in small numbers, like those with which &dquo;spontaneous&dquo; foci have been observed to emerge in colony or control groups of rats (31,35 of developed foci of GST-P-positive hepatocytes (24,36).…”

“…Nonetheless, the BrdU-LIs show that the CDAA diet caused an enhanced and high degree of cell proliferation in females that increased steadily for 12 (28), there appears to be no consensus as yet about their nature and role in lipotrope-deficient diet models (9,14,16,31,35). The major uncertainties stem from the fact that in the latter, enzyme-altered hepatocytes develop in small numbers, like those with which &dquo;spontaneous&dquo; foci have been observed to emerge in colony or control groups of rats (31,35 of developed foci of GST-P-positive hepatocytes (24,36). These findings led to the proposal (15, 24) that 8-OHG may play an important role in the initiation stage of hepatocarcinogenesis by lipotrope-deficient diets, given that this adduct is mutagenic (2,10,21,22), and that specific pathways exist for its removal (3,7,8,18,20), which could be overwhelmed or deteriorated by the high rate of compensatory mitogenesis induced by these diets in the liver of male rats (14,16 …”