title: Ethanol interactions with a choline-deficient, ethionine-supplemented feeding regime potentiate pre-neoplastic cellular alterations in rat liver.
abstract: To examine the effect of ethanol on hepatocarcinogenesis induced by a choline-deficient, ethionine-supplemented (CDE) diet, rats were fed either an ethanol-supplemented diet or ethanol-free, isocaloric diet for 2 months, followed by a CDE diet or control diet for up to 8 months. Changes to cellular composition and pattern of gene expression in the liver were determined at 0 and 3 days, and 1, 2 and 3 weeks after commencing the CDE diet, using histological/immunochemical techniques and northern analysis. Oval cells in the liver were identified morphologically and by expression of pi-glutathione S-transferase (pi-GST), alpha-fetoprotein (AFP) and the embryonic isoform of pyruvate kinase (M2-PK). Oval cell numbers and changes in the pattern of gene expression induced by the CDE diet were accelerated by pre-treatment with ethanol. At all stages, the proportion of oval cells in the test group exceeded that in controls. After 1 week, oval cells had spread sufficiently from the periportal region to be observed pericentrally in test animals and by 3 weeks, extensive formation of ductal structures was apparent, which were absent in controls. Additionally, M2-PK and AFP mRNA were detected earlier, and in greater abundance in animals pre-treated with ethanol. After 8 months of CDE treatment, one or two small hepatic foci (<10 hepatocytes), strongly positive for pi-GST, were detected in the liver of ethanol-pre-treated animals. These foci were absent in CDE-treated animals; however, animals pre-treated with ethanol followed by chronic CDE treatment showed increased size (>40 hepatocytes) and numbers of foci, correlating with the extent of liver damage and varying from 5 to 50% of the liver section. Our data suggest that ethanol pre-treatment potentiates the short-term effects of the CDE diet by enhancing oval cell proliferation, while chronic CDE administration enhances the appearance of pre-malignant hepatic foci that are observed with ethanol pre-treatment alone.
authors.affiliation: Western Australian Institute for Medical Research, Biochemistry and Molecular Biology, School of Biomedical and Chemical Sciences, The University of Western Australia, Crawley 6009, Australia. ecroager@cyllene.uwa.edu.au
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Croager
authors.forename: Patrick G J
authors.initials: PG
authors.lastname: Smith
authors.forename: George C T
authors.initials: GC
authors.lastname: Yeoh
mesh_terms: D000818:Animals; D002796:Choline Deficiency; D019587:Dietary Supplements; D000431:Ethanol / Q000494:pharmacology*; D005001:Ethionine / Q000008:administration & dosage / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology; D011770:Pyruvate Kinase / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D000509:alpha-Fetoproteins / Q000235:genetics
chemical_list: D007527:Isoenzymes; D000509:alpha-Fetoproteins; D000431:Ethanol; D005982:Glutathione Transferase; D011770:Pyruvate Kinase; D005001:Ethionine