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Ketoconazole, omeprazole, and primaquine prolong and enhance the aryl hydrocarbonreceptor signaling induced by the endogenous ligand FICZ
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Several compounds that inhibit cytochrome P4501 (CYP1) enzymes have been shown to actas aryl hydrocarbon receptor (AHR) agonists by reducing the metabolic turnover of the endogenous receptor ligand 6-formylindolo[3,2-b]carbazole (FICZ). In this study we aimed at investigating whether a group of widely prescribed drugs, namely ketoconazole (KTZ),omeprazole (OME) and primaquine (PQ), can act as indirect AHR activators via this mechanism. Inhibitory effects of KTZ, PQ, and OME were measured in CYP1A1 expressing supersomes and all three drugs inhibited CYP1A1 activity. KTZ was the most efficient inhibitor and HPLC analysis revealed that KTZ slowed down the metabolic turnover of intracellular FICZ. All three drugs induced the catalytic activity of CYP1A1 (7-ethoxyresorufin-O-deethylase, EROD) in HaCaT cells as well as increased the expression of CYP1A1 mRNA. Co-exposure to the drugs with FICZ prolonged and enhanced FICZ-induced AHR activation in a synergistic manner. Our findings indicate that KTZ activate AHR by inhibiting the metabolic turnover of FICZ. Interestingly, PQ and OME seem to act by other mechanisms that sensitize the cells to FICZ-dependent transcriptional activation of the AHR.To the author’s knowledge, this is the first publication indicating that KTZ, OME, and PQ can superinduce AHR signaling by increasing the responses to an endogenous receptor ligand.

National Category
Biological Sciences
Research subject
Molecular Bioscience
Identifiers
URN: urn:nbn:se:su:diva-128366OAI: oai:DiVA.org:su-128366DiVA: diva2:914465
Available from: 2016-03-24 Created: 2016-03-24 Last updated: 2016-03-30Bibliographically approved
In thesis
1. The impact of cytochrome P4501-inhibitors on aryl hydrocarbon receptor signaling
Open this publication in new window or tab >>The impact of cytochrome P4501-inhibitors on aryl hydrocarbon receptor signaling
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aryl hydrocarbon receptor (AHR) best known as a ligand-activated transcription factor that mediates toxic responses to xenobiotics such as dioxins, is also activated by certain endogenous compounds. Activation of the AHR up-regulates transcription of a large number of genes, including those encoding members of the cytochrome P450 1 family of enzymes (CYP1s). Although the AHR has been shown to be involved in several normal processes, its physiological role remains elusive. The endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ), formed from tryptophan, is present in cell culture media and biological specimens. FICZ is an excellent substrate for CYP1 enzymes and together FICZ/AHR/CYP1A1 interactions constitute an auto regulatory feedback loop that controls AHR signaling. A vast number of compounds that inhibit CYP1 enzymes have been reported to be AHR activators, even though they have little or no affinity for the receptor. We hypothesized, that their agonistic effects are dependent on the presence of background levels of FICZ. To test this, AHR signaling in different cell systems exposed to FICZ and/or inhibitors was assessed by measuring EROD activity and CYP1A1 transcription. In addition to a commercial culture medium, a medium free of background levels of FICZ was used. Activation of AHR by of a diverse set of CYP1A1 inhibitors did require FICZ in the culture medium. Furthermore, the compounds tested both prolonged and potentiated FICZ-induced receptor signaling. On the basis of these observations we propose that a compound may activate AHR signaling indirectly by inhibiting CYP1A1 and thereby attenuating the metabolism of FICZ. This mechanism was confirmed for certain polyphenols and pharmaceuticals. Surprisingly, the activating capacity and potentiating effect of two pharmaceuticals on AHR signaling could not be explained by the mechanism proposed, and we speculated that in these cases the agonistic effect might involve interactions of the cellular antioxidant response with the basic transcription machinery. Together, our observations provide a mechanistic explanation as to how compounds that inhibit CYP1A1 can activate AHR signaling. They also indicate that the general perception of the binding pocket of AHR as promiscuous, is probably wrong. The fact that indirect activation of AHR may cause sustained signaling requires further studies in vivo not least, in order to prevent toxicity.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2016. 52 p.
National Category
Cell and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-128367 (URN)978-91-7649-385-4 (ISBN)
Public defence
2016-05-13, Atrium, Nobels väg 12 B, Karolinska Institutet, Solna, 10:00 (Swedish)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2016-04-20 Created: 2016-03-24 Last updated: 2016-04-12Bibliographically approved

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