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Title: The role and regulation of the cytochrome P-450 CYP2E subfamily
Author: Freeman, Jonathan Edward
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1993
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Several cytochrome P-450 enzymes are thought to have evolved to metabolise lipophillic xenobiotics allowing subsequent conjugatory and excretory steps to occur. The nature of the metabolic activity of these enzymes and their ability to activate a series of carcinogens has implicated them in carcinogenesis. The CYP2E subfamily activates a series of common carcinogens including N-nitrosodimethylamine (NDMA); situations therefore in which CYP2E levels are elevated may lead to increased carcinogenic risk. A mouse CYP2E cDNA and the single copy CYP2E gene were cloned and characterised and the regulation of CYP2E in this species was studied. Mouse CYP2E protein levels were seen to be elevated by acetone in a variety of tissues; no concomitant increase in CYP2E mRNA was seen. Previous studies in the rat suggested that the CYP2E elevation resulted from substrate induced protein stabilisation. This stabilisation was suggested to be mediated by the presence of the substrate leading to the blocking of a phosphorylation event which may trigger CYP2E protein degradation. This was investigated using mutant forms of the mouse CYP2E protein lacking the phosphorylation site; in mammalian tissue culture systems both mutant and native CYP2E proteins behaved identically suggesting that the protein stabilisational event may be mediated via a mechanism other than the blocking of a phosphorylational change in the CYP2E protein. The CYP2E mRNA and protein became elevated both in the spontaneously diabetic BB/E rat, and the mouse following starvation. As a result of increased β-oxidation in these states ketone body levels become elevated which may lead to stabilisation of the CYP2E protein. Previous studies in chemically induced diabetic rats suggested that the message elevation resulted from the stabilisation of pre-existing CYP2E transcripts; previously characterised events of this kind were seen to be mediated by elements within the 3' untranslated region (UTR) of a message.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available