In vitro toxicity and in silico docking analysis of two novel selective AH-receptor modulators

Show full item record



Permalink

http://hdl.handle.net/10138/247832

Citation

Mahiout , S , Tagliabue , S G , Nasri , A , Omoruyi , I M , Pettersson , L , Bonati , L & Pohjanvirta , R 2018 , ' In vitro toxicity and in silico docking analysis of two novel selective AH-receptor modulators ' , Toxicology in Vitro , vol. 52 , pp. 178-188 . https://doi.org/10.1016/j.tiv.2018.06.010

Title: In vitro toxicity and in silico docking analysis of two novel selective AH-receptor modulators
Author: Mahiout, Selma; Tagliabue, Sara Giani; Nasri, Atefeh; Omoruyi, Iyekhoetin Matthew; Pettersson, Lars; Bonati, Laura; Pohjanvirta, Raimo
Contributor: University of Helsinki, Food Hygiene and Environmental Health
University of Helsinki, Departments of Faculty of Veterinary Medicine
University of Helsinki, Doctoral Programme in Clinical Veterinary Medicine
Date: 2018-06-13
Language: eng
Number of pages: 11
Belongs to series: Toxicology in Vitro
ISSN: 0887-2333
URI: http://hdl.handle.net/10138/247832
Abstract: The mediator of dioxin toxicity, aryl hydrocarbon receptor (AHR), has also important physiological functions. Selective AHR modulators (SAHRMs) share some effects of dioxins, except for their marked toxicity. We recently characterised toxicologically two novel SAHRMs, prodrugs IMA-08401 and IMA-07101 in rats, demonstrating that they are far less deleterious than the most toxic AHR-agonist, TCDD. Here, we analysed the in vitro toxicity and in silico AHR binding of the respective active, deacetylated metabolites, IMA-06201 (N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-06504 (N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). In H4IIE rat hepatoma cells, IMA-06201 and IMA-06504 induced CYP1A1 with comparable potencies and efficacies to those of TCDD. They had little effect on cell viability as assessed by LDH leakage and MTT reduction assays, and were not mutagenic in the Ames test, but IMA-06504 elicited a maximally 2.7-fold increase in micronuclei. Molecular docking simulations showed that similar to TCDD, they occupy the central region of AHR ligand binding cavity. Hence, while showing low to negligible in vitro toxicity, these novel SAHRMs bind to the AHR qualitatively in a similar fashion to TCDD, and appear comparably powerful AHR agonists. Combined with our earlier results demonstrating that they seem considerably less toxic in vivo than TCDD, these compounds are thus highly interesting new SAHRMs.
Subject: AH-receptor
Selective modulators
IMA-06201
IMA-06504
TCDD
Binding modelling
ARYL-HYDROCARBON RECEPTOR
EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
ETHOXYRESORUFIN O-DEETHYLASE
LIGAND-DEPENDENT ACTIVATION
2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN TCDD
OXIDATIVE STRESS
DIOXIN RECEPTOR
GENE-EXPRESSION
CROHNS-DISEASE
HEPATOMA-CELLS
413 Veterinary science
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
1_s2.0_S0887233318302595_main.pdf 1.050Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record