Oral administration of cholic acid promotes growth of liver tumors initiated by diethylnitrosamine in rats.
The effect of dietary administration of cholic acid on tumorigenesis in the liver was investigated in male Fischer-344 rats after carcinogenic initiation by diethylnitrosamine (DEN); progression of liver tumors was examined in the rats fed 0.4% cholic acid-containing diet (CA group) and the rats fed standard diet (C group) at 15, 20 and 25 weeks after administration of DEN. The total bile acids and cholic acid in serum of CA group were 150 nmol/ml and 117 nmol/ml, being 31-fold and 51-fold higher than those in C group (p<0.0001, each). Serum AST and ALT were significantly higher in CA group than in C group at 15 weeks (p<0.01). Serum ALP was significantly higher in CA group than C group at each time point (p<0.01, each). Liver tumors, whose histology was hepatocellular carcinoma, developed at 15 weeks in both CA and C groups. However, tumor volume and tumor weight were significantly increased in CA group, compared to those in C group at each time point (p<0.001, p<0. 001, p<0.01, p<0.001, p<0.01 and p<0.05). The percentage of apoptotic cells in CA group at each time point was significantly lower than C group (p<0.05, p<0.01 and p<0.05). The percentage of bcl-2 positive tumor cells in C group at 20 weeks was 1.88+/-2.59%. However, it dramatically increased to 34.00+/-13.67% in CA group (p<0.0001). It was also higher in CA group than in C group at 15 and 25 weeks (p<0.05 and p<0.01). In addition, the bax-positive cells were higher in CA group than in C group at 20 weeks (p<0.05). These data suggest that oral administration of cholic acid promotes liver tumorigenesis initiated by DEN through reducing apoptosis mediated by overexpression of bcl-2.
Second Department of Internal Medicine, Tottori University School of Medicine, Yonago 683-8504, Japan.
G
G
Shiota
K
K
Oyama
N
N
Noguchi
T
T
Takano
H
H
Ito
H
H
Kawasaki
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D019826:Cholic Acid / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity*; D018450:Disease Progression; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004052:Diethylnitrosamine; D019826:Cholic Acid