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An immunohistochemical and molecular study of putative premalignant liver cell populations induced by Aflatoxin B1

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posted on 15.12.2014, 10:31 by Lucinda Roberta. Weir
Alterations in the phenotypic and genotypic expression in foci of altered hepatocytes (FSH) and tumours in livers of rats treated with aflatoxin B1 (AFB1) were analysed. Expression of the phase I and phase II drug metabolising enzymes, P450 2C11, glutathione S-transferase (GST) 7-7, -glutamyl transferase and novel aldehyde reductase, with high activity towards AFB1-dihydrodiol, were examined. A monoclonal antibody recognising GST Yc2, a phase II enzyme which displays high conjugating activity towards the AFB1-epoxide, was prepared and used to determine its expression in AFB1 treated livers. Tissues were also examined for the presence of genetic mutations in the Ki- and N-ras oncogenes, previously reported as occurring frequently in the livers of AFB1-exposed rats. Codon 243 or the p53 gene, corresponding to codon 249 of the human gene, identified as a mutation "hotspot" in aflatoxin-expressed populations, was also examined. Co-ordinate expression of GST 7-7 and AR was seen in single cells and FAH promptly following treatment, suggesting a similar mechanism of transcriptional control for these proteins. Subsequent induction of GST Yc2 remained increased, despite removal of the carcinogen after twelve weeks. The final tumours were also strongly positive. A mechanism of resistance was confirmed through measurement of the level of AFB1 adducts present in the livers of animals containing high levels of phase II drug metabolising enzymes. No mutations were detected in the ras or p53 genes in the lesions at any of the stages of development examined. These mutations, therefore, cannot be essential in the process of AFB1-induced hepatocarcinogenesis in the rat. The model used more accurately reflects the process of hepatocarcinogenesis occurring in humans following chronic exposure to low levels of AFB1 in the diet than previously published models.


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University of Leicester

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