PROLIFERATION, APOPTOSIS, AND INDUCTION OF HEPATIC TRANSCRIPTION FACTORS ARE CHARACTERISTICS OF THE EARLY RESPONSE OF BILIARY EPITHELIAL (OVAL) CELLS TO CHEMICAL CARCINOGENS

In this study, we used [H-3]thymidine labeling of newly synthesized DN A to examine the earliest effects of 2-acetylaminofluorene (2-AAF) on the mitotic activation of cells in the adult rat liver, and in situ hy bridization analysis to study the expression of three transcription fa ctors (HNF1 beta, HNF3 gamma, and HNF4), and two of the genes (cu-feto protein [AFP] and albumin) regulated by these factors. A low dose of 2 -AAF (and its analogs, 2-AF [2-aminofluorene] and N-OH-2-AAF) elicited a mitogenic response in ductal cells and nondescript periductular cel ls within 24 hours after administration. The compounds also induced th e expression of HNF1 beta, HNF3 gamma, AFP, and albumin in ductal stru ctures but had no detectable effect of HNF4 expression, In contrast, i nitiation of bile duct proliferation by ligation of the common bile du ct had no effect on the expression of these genes in ductal cells. In addition to inducing a mitogenic response, 2-AAF resulted in increased numbers of apoptotic cells in the portal areas, a process that contri buted to overall retention of liver morphology. Our results demonstrat e that 2-AAF and some of its analogs can elicit a specific mitogenic r esponse and induce expression of the ''establishment'' transcription f actors, HNF1 beta and HNF3 gamma, in ductal cells, Our data provide fu rther support of a precursor-product relationship between ''stem-like' ' cells located in ductal structures, oval cells, and hepatocytes.