Regulation of hepatic glutathione synthesis: current concepts and controversies

  title={Regulation of hepatic glutathione synthesis: current concepts and controversies},
  author={Shelly C. Lu},
  journal={The FASEB Journal},
  pages={1169 - 1183}
Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate‐limiting enzyme, γ‐glutamylcysteine synthetase (GCS). In the liver, major factors that determine the availability of cysteine… 

Regulation of glutathione synthesis.

  • Shelly C. Lu
  • Biology, Chemistry
    Molecular aspects of medicine
  • 2009

Crosstalk between cystine and glutathione is critical for the regulation of amino acid signaling pathways and ferroptosis

Cellular cysteine and its derivative GSH cooperate to regulate mTORC1 pathway, the ISR and ferroptosis, further supporting their cooperation in the regulation of cell signaling.

Redox regulation of homocysteine-dependent glutathione synthesis

These studies provide the first evidence for the reciprocal sensitivity of the trans-sulfuration pathway to pro- and antioxidants, and demonstrate that the upstream half of the glutathione biosynthetic pathway is redox sensitive as is the regulation of the well-studied enzymes in the downstream half, namely, γ-glutamyl-cysteine ligase and glutATHione synthetase.

Glutathione and Transsulfuration in Alcohol-Associated Tissue Injury and Carcinogenesis.

The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.

Glutathione in Cancer Cell Death

This review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy.

Expression of glutamate‐cysteine ligase during mouse development

The tissue distribution of Gclc and Gclm transcripts, as well as GCLc protein, in the developing mouse embryo is investigated, and it is found that both mRNAs were highly expressed in the liver and CNS at gestational day 10 and gd 12, with GClm being more abundant than GCLm in the Liver relative to other tissues.

de novo synthesis of glutathione is a prerequisite for curcumin to inhibit HSC activation

It is demonstrated, for the first time, that the antioxidant property of curcumin mainly results from increasing the level of cellular GSH by inducing the activity and gene expression of GCL in activated HSC in vitro.



The regulation of hepatic glutathione.

This work proposes to review some of the recent exciting developments in this field, with a particular focus on the regulation of hepatic GSH, a fairly ubiquitous substance in aerobic life forms and tissues and generally exists in millimolar concentrations.

Increased transcription of the regulatory subunit of gamma-glutamylcysteine synthetase in rat lung epithelial L2 cells exposed to oxidative stress or glutathione depletion.

The present study found that the steady-state mRNA level and the transcription rate of the GCS regulatory subunit also increased under DMNQ-induced oxidative stress, which suggests that, under conditions of oxidative stress or glutathione depletion, the regulatory sub unit is upregulated at the level of mRNA transcription.

Changes in glutathione homeostasis during liver regeneration in the rat

Early in the course of liver regeneration the steady‐state hepatic GSH levels double because of an increase in the biosynthesis of GSH, which can be largely accounted for by the increase in both cysteine availability and the activity of GCS.

Interleukin-1-induced nitric oxide production modulates glutathione synthesis in cultured rat hepatocytes.

In the setting of oxidative stress and IL-1 exposure, hepatocyte synthesis of NO may be protective through regulation of GSH synthesis through a mechanism that is dependent on transcriptional regulation of the rate-limiting enzyme in G SH synthesis.

Insulin and glucocorticoid dependence of hepatic gamma-glutamylcysteine synthetase and glutathione synthesis in the rat. Studies in cultured hepatocytes and in vivo.

Both in vitro and in vivo, In and glucocorticoids are required for normal expression of GCS, the rate-limiting enzyme in GSH synthesis.

Tumor Necrosis Factor Increases Hepatocellular Glutathione by Transcriptional Regulation of the Heavy Subunit Chain of γ-Glutamylcysteine Synthetase*

TNF increases hepatocellular GSH levels by transcriptional regulation of γ-GCS-HS gene, probably through AP-1/metal response element-like binding site(s) in its promoter, which may constitute a protective mechanism in the control of oxidative stress induced by inflammatory cytokines.

Role of the liver in interorgan homeostasis of glutathione and cyst(e)ine.

The principal components and determinants of interorgan homeostasis of GSH and its breakdown products are focused on and the current state of knowledge under both normal and diseased states is presented.

Transforming Growth Factor- β1 Is a Potent Inhibitor of Glutathione Synthesis in the Lung Epithelial Cell Line A549: Transcriptional Effect on the GSH Rate-limiting Enzyme γ -Glutamylcysteine Synthetase

It is observed that TGF-β1 increased susceptibility of the human alveolar epithelial cell line A549 to H2O2-mediated cytotoxicity, and decreased the activities of the antioxidant enzymes glutathione reductase and catalase by 31%, and markedly decreased GSH content in A549 cells.

Nitric Oxide-Dependent Induction of Glutathione Synthesis through Increased Expression of γ-Glutamylcysteine Synthetase

It is proposed that the increase in GSH by NO is a potential mechanism for enhancing the antioxidant defenses of the cell and has important implications for identifying redox-sensitive cell signaling pathways that can be activated by NO.

Transcriptional up-regulation of gamma-glutamylcysteine synthetase gene expression in melphalan-resistant human prostate carcinoma cells.

GCS expression is transcriptionally regulated in these melphalan-resistant tumor cells, suggesting that GSH levels can be accompanied by an increase in the activity of gamma-glutamylcysteine synthetase.