Cell Biology of Nongenotoxic Hepatocarcinogens.

McNae, Fiona. (1994) Cell Biology of Nongenotoxic Hepatocarcinogens. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

An investigation into the early cell biology changes in response to non-genotoxic carcinogens was carried out. The hypolipidaemic drug and peroxisome proliferator, clofibric acid was found to produce a significant hepatomegaly and to induce rat hepatic cytochrome P4504A isozyme(s) and peroxisomal β-oxidation at both the protein and molecular level. Also induced by this compound were the nuclear protooncogenes c-fos and c-myc, both of which are involved in the process of cellular growth control. This compound however, failed to increase transcription of the protooncogenes Ha-ras, Ki-ras, mos, ErbAl. It was concluded that the induction of c-myc and c-fos was related to the observed hepatomegaly and hypothesised that this induction may be characteristic of non-genotoxic carcinogens, in particular, peroxisome proliferators. Therefore, the specificity of this induction to clofibric acid and rat liver was investigated. The transcriptional activation of c-myc, c-fos and c-jun was examined in susceptible and non-susceptible species (rat and guinea pig respectively) and tissues (liver, kidney, heart and lung). The response of these species and tissues to clofibric acid was compared to their response to phenobarbitone. A marked induction of the aforementioned genes was apparent in those tissues which exhibited an increase in cell mass in response to the treatment regimes - there was no such correlation with tissues undergoing organelle proliferation or mixed function oxidase induction. Although the ability of peroxisome proliferators to induce sustained enhancement of cell proliferation correlates with the degree of carcinogenicity (Marsman et al, 1988, Bieri et al, 1986), it was concluded that the early proliferative responses examined here are not exclusively predictive of non-genotoxic carcinogenesis. Recent work has indicated that the Peroxisome Proliferator Activated Receptor (Issemann & Green, 1990) plays a key role in regulation of early gene changes involved in peroxisome proliferator-induced non-genotoxic carcinogenesis. I report the establishment of an in vitro model of peroxisome proliferator-associated effects in our laboratory and the use of this model to substantiate the PPAR-transfection work of Issemann et al (1993). I have demonstrated that the PPAR acts cooperatively with Retinoid X receptor in my in vitro model and dramatically increases the ability of PPAR to cause transcription of specific target genes including constitutive acyl CoA oxidase. In order to examine the regulation of the PPAR itself, one of the potential mechanisms for steroid hormone regulation, namely autoinduction, was investigated. The effect of a series of classical microsomal oxidase inducers (including peroxisome proliferators) on the abundance of PPAR mRNA was examined. My results strongly suggest that PPAR is inducible by those compounds known to be peroxisome proliferators (clofibrate and the perfluorinated fatty acids, PFDA & PFOA). Although no ligand binding to the PPAR has been shown to date, it is possible that the peroxisome proliferators themselves are ligands for the PPAR suggesting an autoregulatory mechanism of PPAR induction. Further, a functional correlation between PPAR induction and CYP4A1 transcription is suggested. It is hypothesised that the involvement of such a feedback loop readily explains the magnitude of enzyme induction response to peroxisome proliferators. The above results were used to draw conclusions as to the early stages of the mechanism of non-genotoxic carcinogenesis with a view to the definition of a diagnostic fingerprint for potential non-genotoxic carcinogens.

Item Type:	Thesis (Doctoral)
Divisions :	Theses
Authors :	McNae, Fiona.
Date :	1994
Additional Information :	Thesis (Ph.D.)--University of Surrey (United Kingdom), 1994.
Depositing User :	EPrints Services
Date Deposited :	06 May 2020 14:06
Last Modified :	06 May 2020 14:09
URI:	http://epubs.surrey.ac.uk/id/eprint/855976

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