Promoting Effects of Bile Acid Load on the Occurrence of Cholangiocarcinoma Induced by Diisopropanolnitrosamine in Hamsters

Abstract

This study was performed to clarify the promoting effects of primary or secondary bile acid load on the occurrence of cholangiocarcinoma, using Syrian golden hamsters. These hamsters received subcutaneously diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and simultaneously were given a standard pellet diet (control group) containing taurocholic acid (TCA group) or deoxycholic acid (DCA group). The rates of cholangiocarcinoma at 20 weeks were 23% in the control group, 60% in the TCA group and 59% in the DCA group. There were significant differences between the control and the TCA or DCA groups (p < 0.05). The rates of proliferation of bile ductules or hyperplasia of the bile duct epithelium and the bromodeoxyuridine labeling indices of bile duct epithelial cells were high in both groups treated with bile acids, compared with those in the control group. Regarding the composition of bile acids in the intraductal bile, the TCA and DCA groups revealed a decrease in primary bile acids and an increase in DCA. These results suggest that both TCA and DCA given orally promote the occurrence of DIPN-induced cholangiocarcinoma.

Bile Acid Load on the DNA Distribution Pattern of Bile Ductules and Cholangiocarcinoma Induced by Diisopropanolnitrosamine in Hamsters

“…Pour et al [24] and Kajikawa et al [25] observed hemangioendothelioma, angiosarcoma or hepatoma, in addition to cholangioma and cholangiocarcinoma. Although hemangioma in the liver and papillary hyperplasia in the gallbladder were observed in some hamsters, the present and previous studies [18] and another study using a similar model [16] revealed no notable neoplasms except bile ductule proliferation and cholangiocarcinoma. The difference in these findings among reports may be due to the methods to produce the model or observation periods.…”

“…These findings indicate the influence of bile acid load on the DNA distribution pattern of cholangiocarcinoma. The results seem to be due to the accelerating effect of DNA synthesis [18] or the promoting effect in mutagenicity [27] of bile acids, especially DCA. Thus, bile acids lead to more increases in DNA content or enhancement of DNA polyploidization implying further malignant transformation.…”

“…Therefore, the role of bile acids in carcinogenesis is attracting the attention of investigators. In previous experiments using hamsters, we demonstrated a promoting effect of bile acid load on the occurrence of diisopropanolnitrosamine (DIPN)-induced cholangiocarcinoma [18]. These animals revealed a definite histological change, consisting primarily of intrahepatic bile ductule proliferation.…”

“…There are some studies demonstrating the promoting effect of DCA or lithocholic acid, one of the secondary bile acids, on cholangiocarcinoma induced by carcinogens [15,16]. In a previous study, we examined the bromodeoxyuridine labeling indices and mitotic indices of proliferated bile ductule cells and carcinoma cells and found that bile acid load, especially DCA, accelerated the DNA synthesis and turnover of their cells [18]. Thus, it has been suggested that DCA in the intrahepatic ductal bile promotes the occurrence of bile ductule proliferation and cholangiocarcinoma induced by DIPN.…”

Chemical and biological analysis of active free and conjugated bile acids in animal bile using HPLC-ELSD and MTT methods

“…notably, we observed a strong and constant stimulation of mhcc97-l cell proliferation by SB, in which tca is the major and only component identified by the HPLC analysis. TCA was found to promote the occurrence of cholangiocarcinoma induced by diisopropanolnitrosamine in hamsters (15), although the exact mechanism needs further investigation.…”