Methionine restriction up‐regulates the expression of the pi class of glutathione S‐transferase partially via the extracellular signal‐regulated kinase‐activator protein‐1 signaling pathway initiated by glutathione depletion

Abstract

Understanding 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 pi 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 muM L-buthionine sulfoximine (BSO) or in a methionine-restricted L-15 medium supplemented with 20 muM 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 NH(2)-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.

Glutathione, glutathione-related enzymes, and oxidative stress in individuals with subacute occupational exposure to lead

“…However, results of the present study indicate that subacute exposure to lead decreases erythrocyte GST activity. Tsai et al (2010) postulated that GSH depletion upregulates the expression of the pi class of GST (GSTP). In the present study, GSH level was also decreased due to lead exposure, thus there must be another mechanism to override this postulated reverse association between GST expression and GSH level resulting in a decreased GST activity in spite of the depletion of the GSH pool.…”

Carnosic Acid Induces the NAD(P)H: Quinone Oxidoreductase 1 Expression in Rat Clone 9 Cells through the p38/Nuclear Factor Erythroid-2 Related Factor 2 Pathway

“…Total RNA was extracted by using Trizol reagent. RT-PCR was performed as previously described (23). The sequences for the RT-PCR primers were as follows: NQO1 (forward: 59-GCACGAATACGGTC-GATTC-39, reverse: 59-GTCGGCTGGAATGGACTTG-39); GAPDH (forward: 59-GACGTGCCGCCTGGAGAAA-39; reverse: 59-GGGGG-CCGAGTTGGGATAG-39).…”

Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

“…Studies examining the restriction of the essential amino acid and glutathione precursor methionine found it not only to be lifespan extending. Increasing mitochondrial biogenesis and function, energy expenditure, stress resistance, aerobic capacity, insulin sensitivity, glutathione (GSH) and expression of glutathione-S-transferase (GST) as well as a decrease of oxidative stress and cell damage due to adaptive changes in methionine and GSH metabolism were also observed (Zimmerman et al 2003, Miller et al 2005, Perrone et al 2010, Richie et al 1994, Malloy et al 2006, Sanz et al 2006, Perrone et al 2012, Tsai et al 2010, Caro et al 2008. Interestingly, co-treatment with an antioxidant, N-acetylcysteine, blocks some of the health-promoting effects of methionine restriction, accentuating a critical role for ROS with mitohormetic adaption processes in this regard (Elshorbagy et al 2012, Sanchez-Roman et al 2012).…”