title: Persistence of the cholangiocellular and hepatocellular lesions observed in rats fed a choline-deficient/DL-ethionine-supplemented diet.
abstract: Male outbred Sprague-Dawley rats were fed a choline-deficient diet containing 0.10% DL-ethionine (CDE) for 4, 6, 10, 14 or 22 weeks followed by a standard diet for up to 59 weeks. Liver sections were histochemically analyzed for the following parameters: basophilia, glycogen content and the activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6PASE), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycerin-3-phosphate dehydrogenase (G3PDH), 'malic enzyme' (MDH), alkaline phosphatase (ALKPASE) and gamma-glutamyltranspeptidase (GGT). The stop experiments revealed that many of the oval cells proliferating during the first 4-6 weeks may undergo necrotic changes and disappear with time, whereas cholangiofibroses appearing in animals fed CDE for at least 10 weeks are persistent lesions. The sequence of lesions seen in this study, leading from persistent oval cells through cholangiofibroses to cholangiofibromas, strongly suggests that the oval cells are the precursor cells of cholangiocellular tumors. The proliferating oval cells and the hepatic foci consisting of clear and acidophilic or mixed cell populations were always spatially separated and no transitions between oval and parenchymal cells were observed. These results argue against a precursor-product relationship between oval and parenchymal cells. Both proliferating and persistent oval cells, cholangiofibroses and cholangiofibromas showed a strong staining for G6PDH, GAPDH, G3PDH, MDH, ALKPASE and GGT; low PHO, SYN and G6PASE activities were also detected in these lesions. Persistent glycogen-storage foci, which developed in all rats fed CDE for 4-14 weeks followed by a normal lab chow for over a year, had increased PHO, G6PDH, MDH, ALKPASE and GGT activities, while SYN, GAPDH and G3PDH activities remained unaltered and G6PASE activity decreased. Mixed cell foci appearing in animals fed CDE for 22 weeks followed by a normal lab chow for 59 weeks had strongly increased G6PDH, GAPDH, G3PDH, MDH, ALKPASE and GGT activities as well as decreased G6PASE activity. These results indicate that the characteristic metabolic pattern of preneoplastic hepatic foci is independent of the further administration of the carcinogenic diet. The shift from glycogen metabolism to glycolysis and the pentose phosphate pathway occurring during the later stages of CDE-induced hepatocarcinogenesis is an autogenous process apparently directing the disturbed carbohydrate metabolism towards alternative metabolic pathways. A similar metabolic shift also seems to take place during cholangiocarcinogenesis.
authors.affiliation: Division of Cytopathology, German Cancer Research Center, Heidelberg.
authors.forename: H J
authors.initials: HJ
authors.lastname: Hacker
authors.forename: P
authors.initials: P
authors.lastname: Steinberg
authors.forename: I
authors.initials: I
authors.lastname: Toshkov
authors.forename: F
authors.initials: F
authors.lastname: Oesch
authors.forename: P
authors.initials: P
authors.lastname: Bannasch
mesh_terms: D002759:Adenoma, Bile Duct / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000473:pathology*; D002794:Choline / Q000008:administration & dosage* / Q000633:toxicity; D005001:Ethionine / Q000008:administration & dosage*; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D051381:Rats; D014166:Transferases / Q000378:metabolism
chemical_list: D010088:Oxidoreductases; D014166:Transferases; D010744:Phosphoric Monoester Hydrolases; D002794:Choline; D005001:Ethionine