The Role of Cytochrome P450 2A5 During Endoplasmic Reticulum Stress

dc.contributor.advisorKirby, Gordon
dc.contributor.authorMorgan, Larry
dc.date.accessioned2014-01-17T19:32:09Z
dc.date.available2014-01-17T19:32:09Z
dc.date.copyright2014-01
dc.date.created2014-01-17
dc.date.issued2014-01-17
dc.degree.departmentDepartment of Biomedical Sciencesen_US
dc.degree.grantorUniversity of Guelphen_US
dc.degree.nameMaster of Scienceen_US
dc.degree.programmeBiomedical Sciencesen_US
dc.description.abstractCytochrome P450 2A5 (CYP2A5) is a murine orthologue of human CYP2A6 and is predominantly found within the endoplasmic reticulum (ER) of the liver. CYP2A5 differs from its P450 counterparts in that it is induced during liver injury caused by hepatitis, liver cancer, and hepatotoxicity. All of these events induce ER stress and protein malfolding, eventually resulting in apoptosis if not rectified. Previous studies have shown that the oxidized form of dithiothreitol (DTTox) induces CYP2A5 in primary mouse hepatocytes while other ER stressors do not, suggesting a reductive ER environment may be associated with its induction. Recently, bilirubin (BR) has been identified as the first endogenous substrate for CYP2A5. Furthermore, BR and its predecessor heme have also been shown to transcriptionally regulate Cyp2a5 and metabolism of BR by CYP2A5 has been shown to provide partial cytoprotection during BR hepatotoxicity. The purpose of this study was to investigate the mechanism of Cyp2a5 gene regulation by reductive stress and to assess the cytoprotective role of CYP2A5 during reductive ER stress. Our results show that the reducing agent 2-mercaptoethanol induces CYP2A5 in a similar manner to DTTox. We also found that DTTox transcriptionally regulates Cyp2a5 via a mechanism that requires the transcription factor Nrf2. Expression of the BR-conjugating enzyme UGT1A1 is also increased after DTTox treatment. Furthermore, hemin induces mRNA splicing of the ER stress-associated transcription factor XBP-1. These data suggest that heme/BR may be playing a role in ER stress-mediated CYP2A5 expression. Finally, our results indicate that CYP2A5 plays a cytoprotective role during DTTox -induced ER stress by reducing XBP-1 mRNA splicing and blocking caspase-3 cleavage.en_US
dc.identifier.urihttp://hdl.handle.net/10214/7827
dc.language.isoenen_US
dc.publisherUniversity of Guelphen_US
dc.rights.licenseAll items in the Atrium are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectCYP2A5en_US
dc.subjectER Stressen_US
dc.subjectHepatocytesen_US
dc.subjectNrf2en_US
dc.subjectHemeen_US
dc.subjectBilirubinen_US
dc.titleThe Role of Cytochrome P450 2A5 During Endoplasmic Reticulum Stressen_US
dc.typeThesisen_US

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