Acetaminophen-induced reduction in glutathione-S-transferase A1 in hepatocytes: A role for hepatic nuclear factor 1α and its response element.

The role of hepatic nuclear factor 1α (HNF-1α) and its response element in the expression of glutathione S-transferase A1 (GSTA1) was investigated in hepatocytes cells injury induced by acetaminophen (APAP). Treatment of hepatocytes with C2-ceramide exacerbated cells injury with GSTA1 mRNA level reducing. Contrastingly, administration of oltipraz alleviated cells damage with GSTA1 mRNA level elevating relative to hepatotoxicity induced by APAP. Western blot analysis showed that C2-ceramide decreased the translocation of HNF-1α and expression of GSTA1 protein, while oltipraz increased nuclear HNF-1α level and transactivation of GSTA1. The role of HNF-1α on GSTA1 expression was confirmed by transfection experiment and dual-luciferase reporter assay system. In the cells transfected with pGSTA1-1298-LUC vector in which HNF-1 response element (HRE) was contained, the luciferase activity decreased with reduction of nuclear HNF-1α and increased with elevation of nuclear HNF-1α. However, the luciferase activity had no change with the variation of nuclear HNF-1α when the cells transfected with the plasmid of pGSTA1-ΔHNF1-LUC in which the HRE was mutated. In conclusion, HNF-1α could affect the transcription of GSTA1 and HNF-1 response element in the GSTA1 promoter region, which is functionally active for the GSTA1 transcription.