A Review of Dietary (Phyto)Nutrients for Glutathione Support

Abstract

Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status.

Keywords: broccoli; cancer prevention; cruciferous vegetables; glutathione; glutathione S-transferase; green tea; nutrigenomics; phytonutrients; plant-based diet; selenium; vitamins.

Figure 1

Hepatic synthesis of glutathione and nutritional substrates, co-factors, and other nutrients that influence metabolism. Key: 5-Methyl-tetrahydrofolate (5MTHF), system alanine–serine–cysteine (ASC), cystathionine-β-synthase (CBS), cystathionine gamma-lyase (CGL), electrophile response element (EpRE), glutathione-S-transferase (GST), glutamate cysteine ligase (GCL), glutathione reductase (GRx), glutathione peroxidase (GPx), glutathione synthetase (GSx), hydrogen peroxide (H₂O₂), Nuclear factor erythroid factor-2-related factor 2 (Nrf2), S-adenosylmethionine (SAMe), S-adenosylhomocysteine (SAH), tetrahydrofolate (THF), thioredoxin reductase 1 (TRR1), water (H₂O), cystine/glutamate antiporter system (x_c⁻). Description: Folic acid is reduced to THF and converted to 5MTHF which can subsequently be transferred to homocysteine and generate methionine. Methionine forms SAMe, which produces SAH from methylation reactions. SAH is hydrolyzed to homocysteine. Homocysteine can either regenerate methionine or be directed to the trans-sulfuration pathway forming cystathionine via the catalytic activity of CBS and serine. CGL cleaves the sulfur–gamma carbon bond of cystathionine, resulting in the release of cysteine which can be used by GCL and GSx to form glutathione. Extracellular cysteine can be either taken up by the cysteine transporter ASC or oxidized to cystine and taken up by system x_c⁻. N-acetylcysteine can donate cysteine or reduce plasma cystine to cysteine. Intracellular cystine is reduced to cysteine via TRR1 or glutathione. The synthesis of γ-glutamyl cysteine is catalyzed by GCL from cysteine and glutamate, and the addition of glycine to γ-glutamyl cysteine via GSx generates glutathione. GPx catalyzes the reduction of H₂O₂ by glutathione and forms reduced glutathione which is then recycled to glutathione by GRx. Glutathione can also form adducts and conjugate xenobiotics via GST. Oxidative stress activates the Nrf2 pathway which induces EpRE-dependent gene expression of enzymes involved in glutathione metabolism, including GCL, GSx, GPx, and GST, to re-establish cellular redox homeostasis. Modified and developed from [10,11,12,13,14].