Inhibition of CYP1A1 by pharmaceutical drugs, omeprazol and ketoconazole as a mechanism for activation of aryl hydrocarbon receptor (AHR)

Document Type : Research(Original) Article



Omeprazole (OMP) and ketoconazole (KTZ) have been shown to activate the AHR signaling pathway in spite of the fact that they bind to the receptor with low or no affinity. The aim of this study was to investigate whether KTZ and OMP can act as indirect activator of AHR. In order to evaluate the effects of KTZ and OMP on AHR signaling, we measured cytochromes p450 (CYP1A1) enzyme activity by ethoxyresorufin-O-deethylase (EROD) assay as endpoint. FICZ, at 1nM concentration, caused a transient elevation in the catalytic activity of CYP 1A1. KTZ and OMP were found to be inducer of CYP1A1 at concentrations above 50 µM. At early time of incubation (3hr), a dose-dependent inhibition of FICZ-induced EROD activity was seen. When OMP or KTZ were added together with FICZ, a prolonged activation of CYP1A1 was observed at later time of incubation (24h). Taken together, our findings support the earlier observation that we shown that CYP 1A1 inhibitors can act as an AHR activator though inhibition of metabolic degradation of FICZ. 


  1. Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals*. Annual review of pharmacology and toxicology. 2003;43(1):309-34.
  2. Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R. Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. Molecular pharmacology. 2006;69(1):140-53.
  3. Hankinson O. Role of coactivators in transcriptional activation by the aryl hydrocarbon receptor. Archives of biochemistry and biophysics. 2005;433(2):379-86.
  4. Hankinson O. The aryl hydrocarbon receptor complex. Annual review of pharmacology and toxicology. 1995;35(1):307-40.
  5. Nebert DW, Dalton TP, Okey AB, Gonzalez FJ. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. Journal of Biological Chemistry. 2004;279(23):23847-50.
  6. Wincent E, Bengtsson J, Bardbori AM, Alsberg T, Luecke S, Rannug U, et al. Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences. 2012;109(12):4479-84.
  7. Wei Y-D, Bergander L, Rannug U, Rannug A. Regulation of CYP1A1 transcription via the metabolism of the tryptophan-derived 6-formylindolo [3, 2-b] carbazole. Archives of biochemistry and biophysics. 2000;383(1):99-107.
  8. Rannug A, Fritsche E. The aryl hydrocarbon receptor and light. Biological chemistry. 2006;387(9):1149-57.
  9. Rannug A, Rannug U, Rosenkranz H, Winqvist L, Westerholm R, Agurell E, et al. Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances. Journal of Biological Chemistry. 1987;262(32):15422-7.
  10. Smirnova A, Wincent E, Vikström Bergander L, Alsberg T, Bergman J, Rannug A, et al. Evidence for new light-independent pathways for generation of the endogenous aryl hydrocarbon receptor agonist FICZ. Chemical research in toxicology. 2015;29(1):75-86.
  11. Wincent E, Amini N, Luecke S, Glatt H, Bergman J, Crescenzi C, et al. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo [3, 2-b] carbazole is present in humans. Journal of biological chemistry. 2009;284(5):2690-6.
  12. Mohammadi-Bardbori A, Vikström Bergander L, Rannug U, Rannug A. NADPH oxidase-dependent mechanism explains how arsenic and other oxidants can activate aryl hydrocarbon receptor signaling. Chemical research in toxicology. 2015;28(12):2278-86.
  13. Mohammadi-Bardbori A, Bengtsson J, Rannug U, Rannug A, Wincent E. Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chemical research in toxicology. 2012;25(9):1878-84.
  14. Mohammadi-Bardbori A, Akbarizadeh AR, Delju F, Rannug A. Chromatin remodeling by curcumin alters endogenous aryl hydrocarbon receptor signaling. Chemico-biological interactions. 2016;252:19-27.
  15. Korashy HM, Shayeganpour A, Brocks DR, El-Kadi AO. Induction of cytochrome P450 1A1 by ketoconazole and itraconazole but not fluconazole in murine and human hepatoma cell lines. Toxicological sciences. 2007;97(1):32-43.
  16. Dzeletovic N, McGuire J, Daujat M, Tholander J, Ema M, Fujii-Kuriyama Y, et al. Regulation of dioxin receptor function by omeprazole. Journal of Biological Chemistry. 1997;272(19):12705-13.
  17. Novotna A, Srovnalova A, Svecarova M, Korhonova M, Bartonkova I, Dvorak Z. Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines. PloS one. 2014;9(6):e98711.
  18. Novotna A, Korhonova M, Bartonkova I, Soshilov A, Denison M, Ashida H. Enantiospecific Effects of Ketoconazole on Aryl Hydrocarbon. 2014.
  19. Daujat M, Peryt B, Lesca P, Fourtanier G, Domergue J, Maurel P. Omeprazole, an inducer of human CYP1A1 and 1A2, is not a ligand for the Ah receptor. Biochemical and biophysical research communications. 1992;188(2):820-5.
  20. Lesca P, Peryt B, Larrieu G, Alvinerie M, Galtier P, Daujat M, et al. Evidence for the ligand-independent activation of the AH receptor. Biochemical and biophysical research communications. 1995;209(2):474-82.
  21. Shiizaki K, Ohsako S, Kawanishi M, Yagi T. Omeprazole alleviates benzo [a] pyrene cytotoxicity by inhibition of CYP1A1 activity in human and mouse hepatoma cells. Basic & clinical pharmacology & toxicology. 2008;103(5):468-75.
  22. Paine MF, Schmiedlin-Ren P, Watkins PB. Cytochrome P-450 1A1 expression in human small bowel: interindividual variation and inhibition by ketoconazole. Drug metabolism and disposition. 1999;27(3):360-4.
  23. Shiizaki K, Ohsako S, Kawanishi M, Yagi T. Identification of amino acid residues in the ligand-binding domain of the aryl hydrocarbon receptor causing the species-specific response to omeprazole: possible determinants for binding putative endogenous ligands. Molecular pharmacology. 2014;85(2):279-89.