Severaal structurally different hypolipidemic compounds and certain phthalate ester plasticizers, the two classes of peroxisome proliferators (PPs) induce, altered areas, neoplastic nodules, and hepatocellular carcinomas in rats and mice after chronic dietary administrtaion. The phenotypic properties of hepatic lesions induced by PPs are signifcantly different from those induced by classical carcinogens. Based on these differences we hypothesize a possible divergence in the mechanism of action by which nomutagenic PPs and classical carcinogens induce liver tumors. We propose that these differences are probably due to a field effect of highly electrophilic reactans of classical carcinogens affecting a variety of genes, whereas the PPs, which probably act by a receptor mediated mechanism, alter the expression of a highly selected set of genes.
The specific aims are: 1) Comparative evaluation of the biologic properties of hepatic lesions in the rat induced by 2 structurally different hypolipidemic peroxisome proliferators, Wy-14,643 and ciprofibrate with those induced by a classical carcinogen by evaluation of: a) phentypic properties, b) functional properties of AA, NN and HCC, and c) autonomous growth properties of AA and NN in the host livers after discontinuation of PP treatment and after transplantaton into syngeneic rats. 2) Examination of NN and HCC induced by PPs, Wy-14,643 and ciprofibrate, and those induced by a classical carcinogen for the expression of genes coding for albumin, alpha- feto-protein, catalase, enzymes of peroxsomal beta-oxidation system, selected phase II drug detoxifying enzymes, DT- diaphorase and epoxide hydrolase by a) measuring mRNA levels using specific cDNA probes, b) examining methylation pattern of AFP, albumin and beta-oxidation enzymes genes using methylation sensitive restriction enzymes, and c) evaluating the amplification of beta-exidation enzyme genes. 3) Examination of Nn and HCC induced by classical genotoxic carcinogens and PPs for differences in the expression of oncogenes compared to one another and to the surrounding normal liver using northern blot analysis and by in situ hybridiation. 4) Identification of oncogene(s) in DNA of HCC induced by PPs using NIH 3T3 cell transformation assay and determination of the mechanism by which they have been activated. 5) Further characterization of HCC of different degree of differentiation and examine for morphological functional properties after a) developing of transplantable tumors, and b) establishing cell lines.
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