Activation of the Aryl Hydrocarbon Receptor (AHR) induces human glutathione S transferase alpha 1 (hGSTA1) expression.

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 (ß-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.

Dexamethasone induces human glutathione S transferase alpha 1 (hGSTA1) expression through the activation of glucocorticoid receptor (hGR).

The glutathione S transferases (GSTs) are a superfamily of isoenzymes that play an important role in xenobiotic and endobiotic detoxification, cellular protection from oxidative stress and modulation of signalling pathways. Human GSTA1 (hGSTA1), a cytosolic isoform, is the most abundant GST in the liver and is involved in the metabolism of carcinogenic compounds, chemotherapeutic agents and lipid peroxidation products. However, the molecular mechanism underlying the regulation of hGSTA1 expression is not well understood. Therefore, the aim of the present study was to better understand the regulation of hGSTA1 gene expression. Putative response elements for several nuclear receptors, including the glucocorticoid receptor (GR), have been identified at the hGSTA1 gene promoter located at -896bp, -863bp and -727bp from the transcription start site. After dexamethasone (DEX) treatment, the GR induces hGSTA1 expression at the transcriptional level. The characterisation of this effect reveals that the GR binds to several glucocorticoid response elements (GREs) located at the hGSTA1 gene promoter. This interaction also results in the transactivation of the hGSTA1 gene promoter together with an increase of the hGSTA1 mRNA levels as well as the protein and activity levels in HepG2 cells. Together, the present results suggest that glucocorticoids have the potential to alter the xenobiotic and endobiotic metabolism mediated by hGSTA1.