How is GSH Maintained in Tissues and Body Fluids?
Homeostatic mechanisms prevent the hepatic GSH content from falling too low. During fasting and starvation, GSH and its precursors are derived from muscle and other tissues. Simple calculations show that the entire human body has no more than a 4-day reserve of GSH so that loss of GSH can become critical in catabolic illness or whenever there is a prolonged period of protein/energy insufficiency. Importantly, GSH declines with age and has a diurnal variation with lowest values in the morning and early afternoon. The diurnal variation is linked to cysteine, and cysteine variation increases in individuals over 60 years. Thus, older individuals have increased vulnerability in cell injury due to both a decline in total amount of GSH and a decline in its homeostatic control.
Most research has focused on tissue levels of GSH, but the difference between GSH needs and availability may be equally important in the extracellular fluids, which bathe cells. GSH is found in all extracellular biological fluids, including plasma, interstitial fluid, cerebrospinal fluid, alveolar lining fluid, saliva, bile, pancreatic fluid, tears, sweat. and urine. The concentration of GSH in body fluids can be up to 1,000-fold lower than found in the tissues, yet all cells appear to release GSH, suggesting a universal requirement for extracellular GSH to protect cell surfaces. In addition, specific functions of extracellular GSH are well described. Bile has a high content of GSH to support detoxification of reactive chemicals in the lumen of the small intestines and to enhance iron absorption. Lipid peroxides are toxic species in the diet that are eliminated by supplemental GSH. GSH in the lining fluid of the lungs eliminates airborne oxidants and helps maintain fluidity of the mucus lining the airways. Elimination of bacteria by pulmonary macrophages in vitro is stimulated by added GSH, but this experiment has not been done in humans in vivo. GSH also protects human lung cells (in vitro) from influenza virus and protects against influenza in mice. One should note that controlled, double-blind studies of these effects have not been done in vivo in humans.
How is GSH Maintained in Tissues and Body Fluids?
GSH is maintained by a continuous cycle of turnover at a rate equivalent to the entire body pool of GSH being made and degraded daily. GSH is synthesized from the precursor amino acids (ie, glutamine, glycine, cysteine) in all tissues. Cells in certain organs (ie, intestines, lung, kidney) can utilize exogenous GSH by a secondary active transport mechanism. Supply of GSH from tissue to extracellular fluids occurs through two types of transporters, classified as MRP and OAT transport proteins. The molecular nature of the systems that allow transport in the opposite direction (from extracellular spaces into cells) is not known. The cycle of GSH release, conversion to precursor amino acids, and resynthesis is termed the “GSH cycle.” Although it was earlier proposed that a “γ-glutamyl cycle” functioned in amino acid uptake, this was found to not be an important mechanism. Disulfide forms of GSH include low molecular weight chemicals and protein-bound forms; under many circumstances, the balance between GSH and these disulfide forms (ie, GSH redox balance) can be more important than the absolute amount of GSH.