Is Genotoxicity of Peroxisome Proliferator-Activated Receptor Agonists Due to Oxidative Stress Via Agonistic Pathways?
Journal Title: Advances in Clinical Toxicology - Year 2021, Vol 6, Issue 4
Abstract
In order to investigate the relationship between genotoxicity and peroxisome proliferator-activated receptor (PPAR) agonistic effects, we conducted two kinds of comet assays (cellular and acellular), a micronucleus (MN) test, and a TK mutation assay with and without PPAR antagonists using human lymphoblastoid cells. PPARα agonist clofibrate (CLF) and PPARγ agonists indomethacin (IND) and pioglitazone (PGZ) showed positive responses in the cellular comet assay, TK mutation assay, and detection of intracellular reactive oxygen species (ROS), but not in the acellular comet assay and MN test. PPARα antagonist (GW6471) suppressed the induction of ROS, DNA damage, and TK mutation by CLF. PPARγ antagonist (BADGE) suppressed the induction of ROS, DNA damage, and TK mutation by IND and PGZ. Therefore, CLF and two PPARγ agonists (PGZ and IND) show genotoxicity by oxidative stress via PPARα and PPARγ agonistic pathways, respectively. Considering that some unrepaired DNA lesions induced by them persist to form gene mutations but not chromosome aberrations, there is a possibility that their genotoxic potential is due to mutagenic but not clastogenic potential by the production of ROS via agonistic pathway
Authors and Affiliations
Kojima H, Nakamura T, Matsumoto K, Hasegawa A, Saito T, Sato K, Honma T, Yamamoto A, Arai H, Kadoma Y, Kawaguchi S, Kikuchi Y and Sasaki YF*
Keywords
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- EP ID EP751936
- DOI 10.23880/act-16000225
- Views 6
- Downloads 0
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