The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates

Abstract

Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1–5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS. A generally underestimated mechanism of action of GSH is its direct nucleophilic interaction with electrophilic compounds yielding thioether GSH S-conjugates. Many compounds, including xenobiotics (such as NAPQI, simvastatin, cisplatin, and barbital) and intrinsic compounds (such as menadione, leukotrienes, prostaglandins, and dopamine), form covalent adducts with GSH leading mainly to their detoxification. In the present article, we wish to present the key role and significance of GSH in cellular redox biology. This includes an update on the formation of GSH-S conjugates or GSH adducts with emphasis given to the mechanism of reaction, the dependence on GST (GSH S-transferase), where this conjugation occurs in tissues, and its significance. The uncovering of the GSH adducts’ formation enhances our knowledge of the human metabolome. GSH–hematin adducts were recently shown to have been formed spontaneously in multiples isomers at hemolysates, leading to structural destabilization of the endogenous toxin, hematin (free heme), which is derived from the released hemoglobin. Moreover, hemin (the form of oxidized heme) has been found to act through the Kelch-like ECH associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway as an epigenetic modulator of GSH metabolism. Last but not least, the implications of the genetic defects in GSH metabolism, recorded in hemolytic syndromes, cancer and other pathologies, are presented and discussed under the framework of conceptualizing that GSH S-conjugates could be regarded as signatures of the cellular metabolism in the diseased state.

Role of Ferroptosis Regulation by Nrf2/NQO1 Pathway in Alcohol-Induced Cardiotoxicity In Vitro and In Vivo

“…It protected cells from damage by free oxides, such as ROS. 29 GSH, a product of cystine/glutamate reverse transporter, also acted as a substrate for GPX4. 30 GPX4 was believed to be a key regulator of ferroptosis.…”

“…Glutathione was a peptide containing cysteine, which was considered to be the main REDOX substance in cells. It protected cells from damage by free oxides, such as ROS . GSH, a product of cystine/glutamate reverse transporter, also acted as a substrate for GPX4 .…”

Prolactin is an Endogenous Antioxidant Factor in Astrocytes That Limits Oxidative Stress-Induced Astrocytic Cell Death via the STAT3/NRF2 Signaling Pathway

“…This aligns with previous research demonstrating STAT3 as a key regulator of astrocyte ROS detoxification and gene expression of antioxidant defenses [ 6 ]. Inhibition of STAT3 significantly reduced basal antioxidant capacity in our study, potentially due to its role in regulating GSH levels, a major contributor to cellular antioxidant capacity [ 67 ]. Supporting this notion, a previous study showed that conditional knockout of STAT3 or pharmacological inhibition of Jak2, which prevents STAT3 activation, results in a significant reduction of GSH levels in astrocytes [ 6 ].…”

Enhancing antioxidant levels and mitochondrial function in porcine oocyte maturation and embryonic development through notoginsenoside R1 supplementation

“…GSH, a major constituent of the non-enzymatic antioxidant system, plays a crucial role in cellular redox balance by scavenging various forms of ROS and reactive nitrogen species (RNS) (Bansal & Simon, 2018;Georgiou-Siafis & Tsiftsoglou, 2023;Kennedy et al, 2020). NRF2 is a major antioxidant transcription factor that plays a key role in regulating redox signalling to maintain redox homeostasis and is involved in a variety of cellular processes (Han et al, 2023;Park et al, 2023;Yang & Smith, 2023).…”