EARLY EVENTS IN CHEMICALLY INDUCED RAT HEPATOCARCINOGENESIS

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The project was initiated to study the sequence of events during chemically induced neoplasia using the rodent hepatoma model in combination with quantitative two-dimensional gel electrophoresis (2D-PAGE). Results obtained to date include: (1) analysis of polypeptide differences between normal rat liver and preneoplastic and neoplastic nodules generated using either the Solt-Farber regimen ("resistant hepatocyte" model) or via feeding the nongenotoxic inducer of peroxisome proliferation, ciprofibrate, revealed few qualitative but numerous quantitative polypeptide differences; (2) polypeptide expression in individual preneoplastic and neoplastic nodules induced via the Solt-Farber protocol or with ciprofibrate was very similar, suggesting a marked "homogeneity" rather than "heterogeneity" of polypeptide expression among the early lesions; (3) all Solt-Farber generated nodules stained strongly both for gamma-gutamyltranspeptidase (GGT) activity and for the placental form of glutathione-S-transferase (GST-P), while in the ciprofibrate induced nodules the expression of GGT and s GST-P was not significantly different than control liver levels; (4) four qualitative polypeptide differnces were noted in Solt-Farber-induced nodules as compared to normal liver. Two of these, polypeptides B (pI 6.25/41 kDa) and C (pI 6.75/24 kDa) were expressed in both ciprofibrate-induced and Solt-Farber-generated preneoplastic and neoplastic nodules. In addition five membrane-associated (5.25/59 kDa, 5/30/33 kDa, 5.25/27 kDa, 6.82/23.5 kDa, and 6.75/21 kDa) and four cytosolic polypeptides (6.20/45 kDa, 5/85/36 kDa, 5.06/34 kDa, 6.00/24 kDa) were coordinately expressed in both preneoplassic and neoplastic nodules from both ciprofibrate and Solt-Farber hepatocarcinogenesis models.