Distinctive intrahepatic biliary adaptation responses occur in the liv
er of rats subjected to select hepatotoxic and/or carcinogenic treatme
nts with the nongenotoxic cholangiocarcinogenic agent furan. Specifica
lly, metaplastic small intestinal-like glands closely resembling in th
eir cellular composition the crypts of Lieberkuhn of normal rat small
intestine were selectively derived from putative hyperplastic bile duc
tule-like progenitor structures in the right and caudate liver lobes o
f young adult Fischer-344 male rats given furan by gavage at a daily d
ose of 30-45 mg/kg body weight, 5 times weekly, over a 2-6-wk treatmen
t period. Longer term chronic administration of furan at 30 mg/kg/day
for 9-19 wk resulted in the preferential development of primary hepati
c adenocarcinomas, which arose at 70-100% incidences from right/caudat
e liver lobes and which were characterized by small intestine mucosal
cell differentiation. Interestingly, the neoplastic glands of these ''
intestinal-type'' hepatic tumors demonstrated strongly positive immuno
chemical reactions for both hepatocyte growth factor/scatter factor an
d its c-met encoded receptor and were immunohistochemically positive f
or transforming growth factor beta(1) (TGF-beta(1)) and for mannose-6-
phosphate/insulin-like growth factor II receptor, implicated in the ac
tivation of latent TGF-beta(1). In contrast, a different pattern of ab
errant bile ductular cell differentiation was noted to occur in the at
rophied right liver lobe of moribund Fischer-344 male rats that were c
hronically exposed over a 10-14-day period to a severely hepatotoxic d
ose of furan (60 mg/kg/day). Under this latter experimental condition,
rare yet distinct cholangiolar-like structures composed of biliary ep
ithelial cells and typically a single ductular hepatocytic cell in var
ious stages of maturation specifically formed in association with an e
xtensive hyperplastic bile ductular reaction. Very similar cholangiola
r-like structures also appeared in areas of preexisting hyperplastic b
ile ductule tissue at 3-5 days following the administration of a singl
e hepatonecrogenic dose of CCl4 to rats that 4-6 wk earlier had been s
ubjected to a bile duct ligation. In addition, a novel rat model was d
eveloped in which furan combined in a unique synergistic manner with b
ile duct ligation to induce the replacement of almost all of liver wit
h well-differentiated hyperplastic bile ductules without evidence of d
ifferentiation along either metaplastic small intestine mucosal cell o
r ductular hepatocyte lineages. Bile ductular epithelial cell isolates
from bile duct-ligated/furan-treated rats were further observed to be
organized in the form of bile duct-like structures in vitro under spe
cific conditions of primary cell culture and in vivo following their c
ell transplantation into the inguinal fat pads of syngeneic recipient
rats. Overall, these findings serve to exemplify the remarkable plasti
city that may be exhibited by certain proliferating biliary cell popul
ations in liver in response to specific types of severe hepatic injury
and/or during cholangiocarcinogenesis.