Activation of the Aryl Hydrocarbon Receptor (AHR) induces human glutathione S transferase alpha 1 (hGSTA1) expression
| Autor: | Eduardo Pérez-Salazar, Guillermo Elizondo, Carmen Martínez-Guzmán, Pedro Cortes-Reynosa, Fátima E. Murillo-González |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Transcriptional Activation Electrophoretic Mobility Shift Assay beta-Naphthoflavone Toxicology 03 medical and health sciences chemistry.chemical_compound Transactivation 0302 clinical medicine Gene expression Humans Enzyme Inhibitors Promoter Regions Genetic Glutathione Transferase biology Base Sequence Promoter General Medicine Glutathione Hep G2 Cells Aryl hydrocarbon receptor Cell biology 030104 developmental biology chemistry Receptors Aryl Hydrocarbon 030220 oncology & carcinogenesis biology.protein Transcription Initiation Site Xenobiotic Glutathione S-Transferase Alpha |
| Zdroj: | Chemico-biological interactions. 331 |
| ISSN: | 1872-7786 |
| Popis: | Glutathione S-transferases (GSTs) are a key enzyme superfamily involved in the detoxification and cytoprotection of a wide variety of xenobiotics, such as carcinogens, anticancer drugs, environmental toxicants, and endogenously produced free radicals. In the liver, the hGSTA1 isoenzyme is the most abundant and catalyzes the glutathione conjugation of a wide range of electrophiles and has been the principal GST responsible for xenobiotic detoxification. Given the critical role of this enzyme in several cellular processes, particularly cell detoxification, understanding the molecular mechanisms underlying the regulation of hGSTA1 expression is critical. Therefore, the aim of the present study was to investigate whether AHR is involved in the modulation of hGSTA1 gene expression and to characterize the molecular mechanism through which AHR exerts this regulation. Two xenobiotic response elements (XREs) were located at -602 bp and -1030 bp from the transcription start site at the hGSTA1 gene promoter. After treatment of HepG2 cells with beta-naphthoflavone (β-NF), an AHR agonist, induction of hGSTA1 mRNA was observed. This effect was mediated by the recruitment of AHR to the hGSTA1 gene promoter and its transactivation, as indicated by the ChIP, EMSA and luciferase activity assays. The increase in hGSTA1 transcription regulated by AHR also resulted in enhanced levels of hGSTA1 protein and activity. Taken together, our data suggest that AHR ligands have the potential to modify xenobiotic and endobiotic metabolism mediated by hGSTA1, thereby altering the detoxification of xenobiotics, steroidogenesis and the efficacy of chemotherapeutic agents. |
| Databáze: | OpenAIRE |
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