Impact of CH223191-Induced Mitochondrial Dysfunction on Its Aryl Hydrocarbon Receptor Agonistic and Antagonistic Activities

Chemical Research in Toxicology
Afshin Mohammadi-BardboriMohammad-Reza Arabnezhad

Abstract

The mechanisms underlying aryl hydrocarbon receptor (AHR) activation by agonists and circumstances that increase the sensitivity toward agonists and AHR inhibition by antagonists are diverse and still not fully understood. AHR antagonist, 2-methyl-2 H-pyrazole-3-carboxylic acid (2-methyl-4- o-tolylazo-phenyl)-amide, CH223191, has been reported to inhibit the AHR transcription activity. However, CH223191 antagonist activity toward an AHR endogenous ligand, 6-formylindolo[3,2- b]carbazole (FICZ), and its mode of action remain to be elusive. Male BALB/c albino mice, HepG2 cells, and HepG2-XRE-Luc carrying cytochrome P4501A1 (CYP1A1) gene linked to a luciferase reporter were exposed to FICZ alone or in combination with CH223191, buthionine-( S, R)-sulfoximine (BSO), and N-acetyl-l-cysteine (NAC) for 5 h. Microsomal and cellular CYP1A1 enzyme activities, cellular FICZ levels, CYP1A1 reporter activity, mitochondrial membrane potential, and mitochondrial-dependent reactive oxygen species (ROS) formation were measured. In this study, we showed that AHR activity induced by an AHR endogenous ligand, FICZ, in a dose-dependent manner could be suppressed by CH223191. Indeed, we observed that CH223191 is able to inhibit the catalytic activit...Continue Reading

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Citations

Sep 24, 2020·Cellular and Molecular Life Sciences : CMLS·Jing-Ru LiuYing-Yong Zhao
Aug 17, 2019·Genes & Development·Niranjan VenkateswaranMaralice Conacci-Sorrell
Nov 26, 2020·American Journal of Physiology. Lung Cellular and Molecular Physiology·Necola GuerrinaCarolyn J Baglole
Sep 25, 2020·European Journal of Medicinal Chemistry·Elizabeth Goya-JorgeRosa M Giner
May 30, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Elizabeth Goya-JorgeMaité Sylla-Iyarreta Veitía

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