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University of Oulu

1. Lämsä, V. (Virpi). Regulation of murine hepatic Cytochrome P450 2a5 expression by transcription factor Nuclear factor (erythroid-derived 2)-like 2.

Degree: 2012, University of Oulu

Abstract The hepatic inducible Cytochrome P450s (CYPs) generally prime xenobiotics for elimination. Murine CYP2A5 and human CYP2A6 share similar xenobiotic substrates and some regulatory features. Recently, they were shown to oxidize bilirubin, a byproduct of heme catabolism and a dose-dependent anti- or pro-oxidant, to biliverdin. In this study, the putative role of the redox-sensitive, cytoprotective transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in the regulation of hepatic Cyp2a5 expression and induction under diverse hepatotoxic conditions and altered heme homeostasis was characterized. The coordination of Cyp2a5 and the Nrf2 target gene Heme oxygenase-1 (Hmox1), which determines bilirubin formation from heme, responses to heavy metals and modulators of heme homeostasis, was studied in cultured wildtype and Nrf2(-/-) mouse primary hepatocytes. Nrf2 was essential for the basal hepatic expression of CYP2A5 in the endoplasmic reticulum (ER) and mitochondria, as well as for its induction by cadmium, lead, methyl mercury and phenethyl isothiocyanate. A functional Nrf2 binding antioxidant response element (ARE) about -2.4 kilobases upstream of the Cyp2a5 transcriptional start site was identified. In contrast to Hmox1, a target of BTB and CNC homology 1 (Bach)-mediated repression via AREs, the regulation of Cyp2a5 did not clearly involve Bach1. Excessive heme induced mainly ER-localized CYP2A5 via Nrf2, which was limited by the Nrf2-independent HMOX1 induction. In heme synthesis blockades, CYP2A5 was enhanced via Nrf2 and additional factors, such as the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). The typical CYP2A5 inducers phenobarbital, dibutyryl-cyclic adenosine monophosphate (db-cAMP) and PGC-1α enhance heme synthesis; CYP2A5 was induced via Nrf2 in acute but not chronic phenobarbital exposure without a clear connection to heme, while the responses to db-cAMP and PGC-1α were sensitized in the absence of Nrf2. This suggests novel crosstalk between Nrf2 and PGC-1α. In this study, Cyp2a5 was identified as a sensitive indicator of hepatic Nrf2 pathway activation that could be used, e.g. for in vitro screening of drug candidate hepatotoxicity. The similar subcellular localization and coordination of CYP2A5 and HMOX1 expression in altered heme metabolism support the postulated role for CYP2A5 in bilirubin homeostasis.

Tiivistelmä Vierasaineet stimuloivat maksan Sytokromi P450 (CYP)-entsyymejä, mikä yleensä lisää niiden eliminaatiota. Hiiren CYP2A5 ja ihmisen CYP2A6 ovat lähisukua katalyyttisten ja osin säätelyllisten yhteneväisyyksiensä puolesta. Vastikään niiden osoitettiin katalysoivan hemin hajoamistuotteen, bilirubiinin hapettumista biliverdiiniksi, mikä saattaisi säädellä sen annosriippuvaisia vaikutuksia antioksidanttina ja oksidanttina. Työssä tutkittiin solustressiä aistivan, suojaavan transkriptiotekijän Nrf2 osuutta Cyp2a5-geenin aktivaatiossa maksatoksisissa olosuhteissa ja hemimetabolian muutoksissa. Cyp2a5:n ja…

Advisors/Committee Members: Hakkola, J. (Jukka).

Subjects/Keywords: Bach1; CYP2A5; HMOX1; Nrf2; PGC-1α; heavy metals; heme homeostasis; hepatotoxicity; liver; redox homeostasis; transcriptional regulation; xenobiotic metabolism; aineenvaihdunta; antioksidantit; entsyymit; geeniekspressio; geenitutkimus; hapettuminen; maksa; markkerit; mitokondriot; oksidantit; raskasmetallit; sytokromit; toksikologia; transkriptio; vierasaineet

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APA (6th Edition):

Lämsä, V. (. (2012). Regulation of murine hepatic Cytochrome P450 2a5 expression by transcription factor Nuclear factor (erythroid-derived 2)-like 2. (Doctoral Dissertation). University of Oulu. Retrieved from http://urn.fi/urn:isbn:9789514299278

Chicago Manual of Style (16th Edition):

Lämsä, V (Virpi). “Regulation of murine hepatic Cytochrome P450 2a5 expression by transcription factor Nuclear factor (erythroid-derived 2)-like 2.” 2012. Doctoral Dissertation, University of Oulu. Accessed January 20, 2021. http://urn.fi/urn:isbn:9789514299278.

MLA Handbook (7th Edition):

Lämsä, V (Virpi). “Regulation of murine hepatic Cytochrome P450 2a5 expression by transcription factor Nuclear factor (erythroid-derived 2)-like 2.” 2012. Web. 20 Jan 2021.

Vancouver:

Lämsä V(. Regulation of murine hepatic Cytochrome P450 2a5 expression by transcription factor Nuclear factor (erythroid-derived 2)-like 2. [Internet] [Doctoral dissertation]. University of Oulu; 2012. [cited 2021 Jan 20]. Available from: http://urn.fi/urn:isbn:9789514299278.

Council of Science Editors:

Lämsä V(. Regulation of murine hepatic Cytochrome P450 2a5 expression by transcription factor Nuclear factor (erythroid-derived 2)-like 2. [Doctoral Dissertation]. University of Oulu; 2012. Available from: http://urn.fi/urn:isbn:9789514299278

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