Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice.
The intracellular transcription factor aryl hydrocarbon receptor (AHR) is bound and activated by xenobiotics, thereby promoting their catabolism by inducing expression of cytochrome P450 oxidase (CYP) genes through binding xenobiotic response elements (XRE) in their promoter region. In addition, it is involved in several cellular pathways like cell proliferation, differentiation, regeneration, tumor invasiveness and immune responses. Several pharmaceutical compounds like benzimidazoles activate the AHR and induce their own metabolic degradation. Using newly generated XRE-reporter mice, which allow in vivo bioluminescence imaging of AHR activation, we show here that the AHR is activated in vivo by teriflunomide (TER), which has recently been approved for the treatment of multiple sclerosis. While we did not find any evidence that the AHR mediates the immunomodulatory effects of TER, AHR activation led to metabolism and detoxification of teriflunomide, most likely via CYP. Mice deficient for the AHR show higher blood levels of teriflunomide, suffer from enhanced thrombo- and leukopenia and elevated liver enzymes as well as from severe gastrointestinal ulcers and bleeding which are lethal after 8-11 days of treatment. Leukopenia, acute liver damage and diarrhea have also been described as common side effects in human trials with TER. These data suggest that the AHR is relevant for detoxification not only of environmental toxins but also of drugs in clinical use, with potential implications for the application of AHR-modifying therapies in conjunction to TER in humans. The XRE-reporter mouse is a useful novel tool for monitoring AHR activation using in vivo imaging.
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: c.redaelli@dkfz-heidelberg.de.
Chiara
C
Redaelli
Department of Chemistry, Institute of Pharmacy and Molecular Biotechnology, Ruprecht Karls University, Heidelberg, Germany. Electronic address: gaffarogullari@uni-heidelberg.de.
Ece Cazibe
EC
Gaffarogullari
Department of Internal Medicine and Clinical Chemistry, University Hospital Heidelberg, Heidelberg, Germany. Electronic address: Maik.Brune@med.uni-heidelberg.de.
Maik
M
Brune
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: c.pilz@dkfz-heidelberg.de.
Caroline
C
Pilz
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: simon.becker@dkfz-heidelberg.de.
Simon
S
Becker
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: j.sonner@dkfz-heidelberg.de.
Jana
J
Sonner
Department of Chemistry, Institute of Pharmacy and Molecular Biotechnology, Ruprecht Karls University, Heidelberg, Germany. Electronic address: jaeschke@uni-hd.de.
Andres
A
Jäschke
Division of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: h.-j.groene@dkfz-heidelberg.de.
Hermann-Josef
HJ
Gröne
DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. Electronic address: wolfgang.wick@med.uni-heidelberg.de.
Wolfgang
W
Wick
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. Electronic address: michael.platten@med.uni-heidelberg.de.
Michael
M
Platten
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Neurology and National Center of Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. Electronic address: t.lanz@dkfz-heidelberg.de.
Tobias Volker
TV
Lanz
D000818:Animals; D003437:Crotonates / Q000097:blood / Q000633:toxicity*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology*; D006885:Hydroxybutyrates; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000503:physiopathology; D009570:Nitriles; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*; D014052:Toluidines / Q000097:blood / Q000633:toxicity*
D003437:Crotonates; D006885:Hydroxybutyrates; D009570:Nitriles; D018336:Receptors, Aryl Hydrocarbon; D014052:Toluidines; C527525:teriflunomide
Aryl hydrocarbon receptor; Cytochrome P450 oxidase; Dug metabolism; Leflunomide (PubChem CID: 3899); Multiple sclerosis; TCDD (PubChem CID:15625); Teriflunomide; Teriflunomide (PubChem CID: 54684141)