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Perfluorinated Carboxylic Acids with Increasing Carbon Chain Lengths Upregulate Amino Acid Transporters and Modulate Compensatory Response of Xenobiotic Transporters in HepaRG Cells.
Lim, Joe Jongpyo; Suh, Youjun; Faustman, Elaine M; Cui, Julia Yue.
Afiliación
  • Lim JJ; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
  • Suh Y; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
  • Faustman EM; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington.
  • Cui JY; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington juliacui@uw.edu.
Drug Metab Dispos ; 50(10): 1396-1413, 2022 10.
Article en En | MEDLINE | ID: mdl-34857530
ABSTRACT
Perfluorinated carboxylic acids (PFCAs) are widespread environmental pollutants for which human exposure has been documented. PFCAs at high doses are known to regulate xenobiotic transporters partly through peroxisome proliferator-activated receptor alpha (PPARα) and constitutive androstane receptor (CAR) in rodent models. Less is known regarding how various PFCAs at a lower concentration modulate transporters for endogenous substrates, such as amino acids in human hepatocytes. Such studies are of particular importance because amino acids are involved in chemical detoxification, and their transport system may serve as a promising therapeutic target for structurally similar xenobiotics. The focus of this study was to further elucidate how PFCAs modulate transporters involved in intermediary metabolism and xenobiotic biotransformation. We tested the hepatic transcriptomic response of HepaRG cells exposed to 45 µM of perfluorooctanoic acid, perfluorononanoic acid, or perfluorodecanoic acid in triplicates for 24 hours (vehicle 0.1% DMSO), as well as the prototypical ligands for PPARα (WY-14643, 45 µM) and CAR (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime [CITCO], 2 µM). PFCAs with increasing carbon chain lengths (C8-C10) regulated more liver genes, with amino acid metabolism and transport ranked among the top enriched pathways and PFDA ranked as the most potent PFCA tested. Genes encoding amino acid transporters, which are essential for protein synthesis, were novel inducible targets by all three PFCAs, suggesting a potentially protective mechanism to reduce further toxic insults. None of the transporter regulations appeared to be through PPARα or CAR but potential involvement of nuclear factor erythroid 2-related factor 2 is noted for all 3 PFCAs. In conclusion, PFCAs with increasing carbon chain lengths up-regulate amino acid transporters and modulate xenobiotic transporters to limit further toxic exposures in HepaRG cells. SIGNIFICANCE STATEMENT Little is known regarding how various perfluorinated carboxylic acids modulate the transporters for endogenous substrates in human liver cells. Using HepaRG cells, this study is among the first to show that perfluorinated carboxylic acids with increasing carbon chain lengths upregulate amino acid transporters, which are essential for protein synthesis, and modulate xenobiotic transporters to limit further toxic exposures at concentrations lower than what was used in the literature.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácidos Carboxílicos / Contaminantes Ambientales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácidos Carboxílicos / Contaminantes Ambientales Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2022 Tipo del documento: Article