Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice

TY - JOUR

T1 - Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice

AU - Redaelli, Chiara

AU - Gaffarogullari, Ece Cazibe

AU - Brune, Maik

AU - Pilz, Caroline

AU - Becker, Simon

AU - Sonner, Jana

AU - Jäschke, Andres

AU - Gröne, Hermann-Josef

AU - Wick, Wolfgang

AU - Platten, Michael

AU - Lanz, Tobias Volker

N1 - Copyright © 2015 Elsevier Inc. All rights reserved.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

KW - Animals

KW - Crotonates/blood

KW - Encephalomyelitis, Autoimmune, Experimental/physiopathology

KW - Mice

KW - Mice, Inbred C57BL

KW - Multiple Sclerosis/physiopathology

KW - Receptors, Aryl Hydrocarbon/genetics

KW - Toluidines/blood

U2 - 10.1016/j.bcp.2015.08.111

DO - 10.1016/j.bcp.2015.08.111

M3 - SCORING: Journal article

C2 - 26341389

VL - 98

SP - 484

EP - 492

JO - BIOCHEM PHARMACOL

JF - BIOCHEM PHARMACOL

SN - 0006-2952

IS - 3

ER -