Dietary Glycine Is Rate-Limiting for Glutathione Synthesis and May Have Broad Potential for Health Protection

Abstract

Background: Glutathione is a key scavenging antioxidant that opposes the proinflammatory signaling of hydrogen peroxide. Boosting cellular glutathione levels may have broad utility in the prevention and treatment of disorders driven by oxidative stress. Supplemental N-acetylcysteine has been employed for this purpose. Could supplemental glycine likewise promote glutathione synthesis?

Methods: We conducted a review of the pertinent literature using PubMed.

Results: Tissue glycine levels are lower than the glutathione synthase Michaelis constant (K_m) for glycine. When glycine availability is too low to sustain a normal rate of glutathione synthesis, the consequent rise in tissue levels of gamma-glutamylcysteine leads to an increase in urinary excretion of its alternative metabolite 5-L-oxoproline. The fact that urinary excretion of this metabolite is elevated in vegetarians and others consuming relatively low-protein diets strongly suggests that dietary glycine can be rate-limiting for glutathione synthesis in normally fed humans. Moreover, supplemental glycine has been reported to increase tissue glutathione levels in several animal studies. Glycine is a biosynthetic precursor for porphyrins, purines, creatine, sarcosine, and bile salts; is an agonist for glycine-gated chloride channels and a coagonist for N-methyl-D-aspartate receptors; inhibits protein glycation; and increases hepatic production of pyruvate, an effective scavenger of hydrogen peroxide. Supplemental glycine may have the potential for improving endothelial function, preventing cardiac hypertrophy, aiding control of metabolic syndrome, preventing the complications of diabetes, dampening inflammation, protecting the liver, and promoting effective sleep.

Conclusion: Clinical research is warranted to evaluate the impact of supplemental glycine on glutathione levels and on various health disorders.

Keywords: Acetylcysteine; chloride channels; glucagon; glucagon-like peptide 1; glutathione; glutathione synthase; glycine.

Figure

Dose-response associations between (log-transformed) plasma glycine and risk of acute myocardial infarction. Generalized additive regressions are used with the adjustment for age and sex in the simple model (A) and with additional adjustment for smoking, obesity, hypertension, diabetes mellitus, angiographic extent of coronary artery disease (ordinal), estimated glomerular filtration rate, apolipoprotein A-1, apolipoprotein B, and statin treatment in the multivariate model (B). The solid lines and the shaded areas represent hazard ratios of plasma glycine and their 95% confidence intervals, respectively. The areas under the curve along the x-axes represent the distributions of the plasma glycine concentrations (μmol/L) in the total population. The vertical white lines denote the 25th, 50th, and 75th percentiles of plasma glycine, respectively. (Republished with permission according to a Creative Commons Attribution-NonCommercial license; Ding et al.⁷⁰)