Glutathione homeostasis is significantly altered by quercetin via the Keap1/Nrf2 and MAPK signaling pathways in rats

Abstract

Previously, we showed that 0.5% quercetin simultaneously decreased serum homocysteine and glutathione (GSH) levels in rats. The aim of the present study was to investigate the effects of 0.5% quercetin on GSH metabolism, related enzymes and signal pathways in rats. Rats were fed the control diet and 0.5% quercetin-supplemented diet for 6 weeks. The results showed that quercetin reduced serum and hepatic content of GSH and the ratio of GSH and oxidized glutathione (GSSG), enhanced hepatic activity and mRNA expression of glutathione S-transferase (GST), inhibited hepatic activity and mRNA expression of glutamate cysteine ligase (GCL), and decreased hepatic glutathione reductase (GR) mRNA expression. Levels of phosphorylated p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinases (MAPKs) increased, while that of nuclear factor E2-like 2 (Nrf2) protein decreased after quercetin treatment. However, no significant hepatotoxicity was noted. We concluded that quercetin treatment altered hepatic GSH metabolism by modulating GSH metabolic enzyme activities and mRNA expression in rats, and p38, ERK1/2 MAPKs, and Nrf2 were involved in modulating GSH metabolism-related enzymes.

Antioxidant Activities of Quercetin and Its Complexes for Medicinal Application

“…Thus, the dynamic balance of GSH is produced, which may cause the inhibition of GSH levels in low doses. This inhibition of quercetin on GSH at the level of 0.5% is reported in the literature [16].…”

Chemical screen identifies a geroprotective role of quercetin in premature aging

“…In addition, we have recently demonstrated that, the premature aging phenotypes in HGPS hMSCs partially attributes to the repression of NRF2-mediated anti-oxidative response, whereas the reactivation of NRF2 reverses the nuclear defects in HGPS cells and restores their in vivo viability in mice (Fang et al, 2018 ; Kubben et al, 2016 ). Interestingly, Que is reported as an activator of NRF2-mediated anti-oxidative pathway (Bahar et al, 2017 ; Dai et al, 2018 ; Gao et al, 2018 ; Kim et al, 2018 ). Consistently, by RNA-seq analysis we identified that Que upregulated a series of anti-oxidative genes including GSTP1 , GSR and GSTM1 , all of which are NRF2 targets, indicating that Que may exert anti-oxidative effect via the activation of NRF2.…”

Effect of Quercetin on Dexamethasone-Induced C2C12 Skeletal Muscle Cell Injury

“…In human aortic endothelial cells, quercetin affects glutathione levels and redox ratio regulation not through oxidation but through the formation and cellular export of quercetin-glutathione conjugates and upregulation of glutamate-cysteine ligase extracellular quercetin-glutathione conjugates [ 30 ]. Furthermore, quercetin alters hepatic GSH metabolism by modulating GSH metabolic enzyme activities via p38, ERK1/2 MAPKs, and Nrf2 pathways in rats [ 31 ]. Studies have demonstrated that polyphenols could reduce dexamethasone-induced muscle atrophy and downregulate muscle atrophy-related proteins such as ubiquitin ligase atrogin-1 and MuRF-1 [ 32 , 33 ].…”