KAI-LI LIU2026-10-162026-10-162010-06-01Pure ID: 14939203Pure UUID: dc22e221-507f-413d-9481-06e2f58df73110.1002/mnfr.200900083https://www.scopus.com/pages/publications/77953971974https://scholars.csmu.edu.tw/handle/123456789/34014Understanding the molecular events underlying gene regulation by amino acids has attracted increasing attention. Here, we explored whether the mechanism by which methionine restriction affects the expression of the p class of glutathione S-transferase (GSTP) is related to oxidative stress initiated by glutathione (GSH) depletion. Rat primary hepatocytes were cultured in an L-15-based medium in the absence or presence of 200 μM L-buthionine sulfoximine (BSO) or in a methionine-restricted L-15 medium supplemented with 20 mM L-methionine up to 72 h. BSO and methionine restriction time-dependently induced GSTP mRNA and protein expression in a similar pattern accompanied by a decrease in the cellular GSH level. The phosphorylation of extracellular signal-regulated kinase (ERK), but not of c-Jun NH2-terminal kinase and p38, was stimulated by methionine restriction and BSO. Electromobility gel shift assay showed that the DNA-binding activity of nuclear activator protein-1 (AP-1) increased in cells exposed to methionine restriction or BSO. With the ERK inhibitor FR180204, AP-1 activation and GSTP expression were abolished. Moreover, the induction of GSTP by methionine restriction and BSO was reversed by GSH monoethyl ester and N-acetylcysteine. Our results suggest that methionine restriction up-regulates GSTP gene expression, which appears to be initiated by the ERK-AP-1 signaling pathway through GSH depletion in rat hepatocytes.10enjournal article