Epigenetic modifications control CYP1A1 Inducibility in human and rat keratinocytes.

Autor: Lin LW; Department of Environmental Toxicology, University of California, Davis, CA 95616, USA. Electronic address: lowlin@ucdavis.edu., Ehrlich AK; Department of Environmental Toxicology, University of California, Davis, CA 95616, USA., Rice RH; Department of Environmental Toxicology, University of California, Davis, CA 95616, USA. Electronic address: rhrice@ucdavis.edu.
Jazyk: angličtina
Zdroj: Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2025 Jan; Vol. 494, pp. 117163. Date of Electronic Publication: 2024 Nov 22.
DOI: 10.1016/j.taap.2024.117163
Abstrakt: Serially passaged rat keratinocytes exhibit dramatically attenuated induction of Cyp1a1 by aryl hydrocarbon receptor ligands such as TCDD. However, the sensitivity to induction can be restored by protein synthesis inhibition. Previous work revealed that the functionality of the receptor was not affected by passaging. The present work explored the possibility of epigenetic silencing on CYP1A1 inducibility in both rat and human cells. Use of an array of small molecule epigenetic modulators demonstrated that inhibition of histone deacetylases mimicked the effect of protein synthesis inhibition. Consistent with this finding, cycloheximide treatment also reduced histone deacetylase activity. More importantly, when compared to human CYP1A1, rat Cyp1a1 exhibited much greater sensitivity toward epigenetic modulators, particularly inhibitors of histone deacetylases. Other genes in the aryl hydrocarbon receptor domain showed variable and less dramatic responses to histone deacetylase inhibitors. These findings highlight a potential species difference in epigenetics that must be considered when extrapolating results from rodent models to humans and has implications for xenobiotic- or drug-drug interactions where CYP1A1 activity plays an important role.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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