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Title: Xenobiotic regulation of cytochrome P450 gene expression
Author: Smith, Gillian
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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Cytochromes P450 (P450) are a ubiquitous class of monooxygenases located in the endoplasmic reticulum of mammalian cells. These enzymes catalyse the Phase I oxidative metabolism of a wide range of structurally diverse chemicals resulting in increased hydrophilicity and excretion. Certain chemicals are, however, metabolically activated by cytochrome P450, leading to the formation of cytotoxic and/or carcinogenic metabolites. This has been exploited in the design of many prodrugs, including anti-tumour agents, which are inactive as administered but become active in vivo following metabolism by one or more of the P450 isozymes. The regulation of P450 gene expression has been well documented in experimental animals, but at present there is very little information available about the regulation of human P450 genes, particularly in extra-hepatic tissues. Regulation of P450 expression by a range of xenobiotics, known to have profound effects on the expression of rodent P450 genes, has been studied in a mouse model and in cultured cells. Of particular interest were the potent and pleiotropic effects on murine P450 expression of TCPOBOP (1,4 bis [s,(3,5-dichloropyridyloxy)] benzene), which showed marked tissue and species specificity in its inductive effects in rodents. A model was developed, using human tumours grown as xenografts in immune deficient mice, in which the in vivo regulation of human P450 genes could be examined. TCPOBOP was shown to be equally effective at influencing human P450 gene expression and, in most cases, the patterns of gene regulation observed in experimental animals were also seen in the human tumours. These studies suggest that modulation of intra-tumour P450 levels by agents such as TCPOBOP may lead to enhanced metabolism of anticancer drugs such as cyclophosphamide, which require P450-mediated activaion in order to exert their anti-tumour effects.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available