OP-35 - Glutathione S-transferase P influences the Nrf2-dependent control of cellular glutathione metabolism

Abstract

Glutathione-S-transferase P-1 (GSTP) was recently proposed to interact with Nrf2 thus regulating its transcriptional activity. The possible consequences of such functional interaction on the metabolism and redox of cellular GSH remain unexplored and were investigated for the first time in this study using both genetic and pharmacological manipulation models of GSTP in murine embryonic fibroblasts (MEFs). The GSTP-/- genotype was associated with a higher nuclear translocation of Nrf2 and apoptotic signaling of MEFs, and then with a marked increase of Cys uptake that resulted in a higher de novo biosynthesis and secretion of cellular GSH. Se-organic compounds (SOC) further stimulated these responses with a potency that correlated with the thiol peroxidase activity of the compounds. A defective expression of GSTP and SOC treatments also influenced the oxidation of GSH to GSSG and protein glutathionylation (PSSG) that was confirmed to be a GSTP-dependent process. The transient manipulation of Nrf2 gene interfered with the SOC-stimulated synthesis and secretion of GSH in the GSTP-/- aplotype, but not in GSTP+/+ cells. In conclusion, the GSTP-Nrf2 interaction strongly influences the metabolism and redox-signaling function of cellular GSH.