Gene expression changes induced by the tumorigenic pyrrolizidine alkaloid retrorsine in liver of F344 rats

Jewaid, Enas Essam (2011) Gene expression changes induced by the tumorigenic pyrrolizidine alkaloid retrorsine in liver of F344 rats. Masters thesis, Memorial University of Newfoundland.

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Abstract

Pyrrolizidine alkaloids (PAs) are naturally occurring chemical compounds which are found in various plant species worldwide. Although not all PAs are toxic, retrorsine is another representative retrorncine-type PAs consider as one of the most toxic member of the PAs family which has historically received most of the attention to have a genotoxic, hepatotoxic effects on animals and a serious health problem to human as a veno occlusive disease and liver cancer. The mechanism of hepatotoxicity induced by PAs in which PAs convert to the toxic form in the liver has been extensively studied. It has been shown that a genotoxic mechanism is correlated to the tumorigenicity of retrorsine through the formation of the DHP-derivaed DNA adducts. Cytochrome P450 is playing an essential key role in mechanism of liver genotoxicity. The genotoxicity activity of PAs has made them targets for studies designed to determine genes involved in the metabolic actiavation of retrorsine. Microarray studies are now playing a powerful approach in gene expression and discovery. Hence, to better understanding the mechanism of genotoxic effects of retrorsine treated rats, this microarray analysis together with the real time PCR provide qualification and quantification information of the liver metabolizing enzymes activities, including those of the cytochrome P450 enzymes, and identification of genes involved in liver cancer induced by retrorsine treatment. The present study represents the first in vivo examination of chronic transcriptional response of the liver to retrorsine exposure. The available evidence on the metabolism and target-tissue specificity for retrorsine's tumorigenesis suggests that active metabolites of retrorsine interact with endothelial cells in the liver which cause cell toxicity, followed by compensatory proliferation of DNA-damaged endothelial cells causing mutations in these cells. We have identified 53 genes in the liver of retrorsine-treated rats that were differentially expressed. Our findings suggest that these genes may play an important role in the metabolism of retrorsine. The genes identified in this study are involved in many diverse processes, including apoptosis, angiogenesis, cell growth, cell death, adhesion, and cell movement of endothelial cells, oxidative stress, liver development, catalytic activity, and signal transducer activity. P450 2E1 enzyme is the major metabolizing enzymes responsible for metabolism of retrorsine which was confirmed to be increased in gene expression by Real-Time PCR, these findings suggest that pyrrolizidine alkaloids retrorsine is metabolically activated by P450 2E1 to form chemically reactive dehydrogenated intermediates.

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