Daniela Rahmel
Investigations of gene expression and metabolic activity of the human respiratory nasal mucosa
The objective of this study was to characterize the expression of xenobiotic metabolizing enzymes as well as the metabolic capacity of the human respiratory nasal mucosa. In particular, the various isoforms of the cytochrome P450 monooxygenases (CYPs) were investigated. The respiratory nasal mucosa samples were taken from patients who had undergone a partial turbinectomy of the lower nasal concha after mucosal hyperplasia had been diagnosed.
Several cytochrome P450 monooxygenases could be identified using RT-PCR, including CYP 1A1, 1B1, 2A6/7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2E1, 2F1, 2J2, 2S1, 3A4, 3A5 and 4B1, albeit at different expression levels. The enzymes CYP 1A2, 2D6, 3A7 and 4A11 were below the limit of quantification. Furthermore, the expression of epoxide hydrolase (EH), the flavin containing monooxygenases 2, 3 and 5 (FMO 2, FMO 3 and FMO 5), the glutathione-S-transferases α2, µ1 and ρ1 (GST α2, GST µ1 and GST ρ1) as well as the UDP-glucuronyltransferase 2A1 (UGT 2A1) could be demonstrated in human respiratory nasal mucosa. Abundant expression of CYP 1A1, 1B1 and 2S1 was found in patients that smoked, while GST α2 was expressed at lower levels in these patients. Male patients showed a higher expression level of CYP 2J2 than female patients, otherwise no other sex-related differences were observed. Immune reactive CYP 2A protein was confirmed by Western blot analysis, but not CYP 1A1, 2B6, 2E1, 3A4 or 3A5 protein. In microsomal assays with pooled nasal concha, the CYP 1A substrate ethoxyresorufin was not metabolized, while testosterone and loteprednol-etabonate (LE) were metabolized to a limited extent.
Thus, the expression of several CYP isoforms could be demonstrated in human respiratory nasal mucosa, although only the CYP 2A protein appeared to be translated. The metabolic activities shown for testosterone and loteprednol-etabonate were markedly lower in nasal mucosa than in the liver. The drug loteprednol-etabonate was found to undergo only minimal metabolism in the experiments conducted with human nasal microsomal preparations, and for this reason may be suitable for therapy using local administration on the nasal mucosa in man.
7. Danksagung
Mein Dank gilt in erster Linie dem Institut für Toxikologie und Experimentelle Medizin der Fraunhofer Gesellschaft, das durch die Bereitstellung der Räumlichkeiten, Geräte und Materialien die Voraussetzung für diese Dissertation geschaffen hat.
Bei Herrn Prof. Dr. Borlak möchte ich mich für die wissenschaftliche Betreuung bedanken, ebenso bei Herrn Prof. Dr. Otto, der freundlicherweise das Koreferat von Seiten der Tierärztlichen Hochschule Hannover übernommen hat.
Prof. Dr. Lamm und Dr. Lamm sowie dem gesamten OP-Team des Friederiken-Stifts Hannover danke ich für die Unterstützung beim Sammeln der Nasenmuscheln, ohne deren Hilfe dieses Projekt nicht zustande gekommen wäre.
Bei allen technischen Assistenten der Abteilung bedanke ich mich dafür, dass sie mir stets mit Rat und Tat zur Seite gestanden haben. Dies waren insbesondere Marlies und Antje, die mir beim Sammeln der Nasenmuscheln geholfen haben, Rong und Kerstin, die mich in die Methodik der RT-PCR eingewiesen haben, Andrea, die mir die Western blots näher gebracht hat, sowie Gitta, die mir im Rahmen der metabolischen Assays bei der Durchführung und der anschließenden Auswertung behilflich war.
Den Post-docs Thomas Thum, Tanja Hansen und Volker Zelinski möchte ich für die Unterstützung bei der jeweiligen Versuchsplanung, -durchführung und -auswertung danken.
Herrn Dr. Holländer bin ich für die statistische Auswertung und seine ausführlichen Erläuterungen zu Dank verpflichtet.
Prof. Dr. Richter danke ich für die Bereitstellung der Aufnahmen der histologischen Schnitte eines Patienten mit allergischer Rhinitis.
Bei Frau Ockert möchte ich mich für die Hilfe bei der englischen Übersetzung bedanken.
Bei meinen Eltern bedanke ich mich für die moralische und finanzielle Unterstützung. Mein besonderer Dank gilt dabei meinem Vater, der durch seine Sicht als Chemiker und durch die stets sachlichen Diskussionen zur Klärung vieler Fragen beigetragen hat. Darüber hinaus möchte ich allen meinen Freunden danken, die stets ein offenes Ohr für mich hatten und mich immer im richtigen Moment wieder motiviert haben.
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