Zvýšené hladiny
Cysteine
- Essential amino acid in
- Premature and newborn infants
- Subjects stressed by disease [1]
- Intracellular pool of cysteine is relatively small
- Compared pool of GSH in cells
- Cysteine is generally the limiting amino acid for GSH synthesis in humans, as in rats, pigs, and chickens [1]
- Cysteine is readily oxidized to cystine in oxygenated extracellular solutions
- Plasma concentration of
- Cysteine (10–25 µmol/L)
- Cystine (50–150 µmol/L) [1]
Cysteine and cystine
- Transported by distinct membrane carriers [1]
Játra
- Some cell types (e.g., hepatocytes) have little or no capacity for direct transport of extracellular cystine
- But GSH that effluxes from the liver
- Can reduce cystine to cysteine on the outer cell membrane
- Resulting cysteine is taken up by hepatocytes [1]
Problém je, když se někdo předávkovává paralenem !!!
Endotel
- Can take up cystine and reduce it intracellularly to cysteine
- Cellular reducing conditions normally favor the presence of cysteine in animal cells [1]
Glutamin
- Rat erythrocytes do not take up or release glutamate
- Glutamine and/or BCAAs may be the precursors of glutamate in these cells
- Glutamine is an effective precursor of the glutamate for GSH synthesis in many cell types
- Enterocytes,
- Neural cells,
- Liver cells,
- Lymphocytes [1]
- Glutamine supplementation to total parenteral nutrition
- Maintains tissue GSH levels
- Improves survival after reperfusion injury, ischemia, acetaminophen toxicity, chemotherapy, inflammatory stress, and bone marrow transplantation [1]
Methionin
- Cysteine generated from methionine catabolism
- Via the transsulfuration pathway (primarily in hepatocytes) - B12 !!!
- Serves as a substrate for GCS
- Dietary methionine can replace cysteine to support GSH synthesis in vivo [1]
High glutamate concentration intracelulárně
- GSH is a nonallosteric feedback inhibitor of GCS
- Binding of GSH to the enzyme competes with glutamate
- When intracellular glutamate concentrations are unusually high
- As in canine erythrocytes
- GSH synthesis is enhanced and its concentration is particularly high [1]
Glutamát
- Extracellular and intracellularly generated glutamate
- Can be used for GSH synthesis
- Dietary glutamate is almost completely utilized by the small intestine
- Plasma glutamate is derived primarily from its de novo synthesis and protein degradation
- Glutamate plays a regulatory role in GSH synthesis through two mechanisms
- Uptake of cystine
- Prevention of GSH inhibition of GCS [1]
Glutamate formation
- Phosphate-dependent glutaminase
- Glutamate dehydrogenase
- Pyrroline-5-carboxylate dehydrogenase
- BCAA transaminase
- glutamine:fructose-6-phosphate transaminase [1]
Glycine availability
- May be reduced in response to:
- protein malnutrition
- Sepsis
- Inflammatory stimuli
- Hepatic glycine oxidation is enhanced in response to high levels of glucagon or diabetes
- May become a limiting factor for GSH synthesis
- In vivo studies - glycine availability limits erythrocyte GSH synthesis in
- Burned patients
- Children recovering from severe malnutrition
- Dietary glycine supplementation enhances the hepatic GSH concentration
- In protein-deficient rats challenged with TNF-alpha [1]
- Dietary amino acid balance has an important effect on protein nutrition
- Therefore on GSH homeostasis [1]
High glutamate concentration extracelulárně
- Glutamate and cystine share the system Xc- amino acid transporter
- When extracellular glutamate concentrations are high
- As in patients with advanced cancer, HIV infection, and spinal cord or brain injury
- As well as in cell culture medium containing high levels of glutamate
- Cystine uptake is competitively inhibited by glutamate
- Resulting in reduced GSH synthesis [1]
Insulin and growth factors
- Stimulate cysteine (cystine) uptake by cells
- Generally increase intracellular GSH concentrations [1]
Nuclear factor ?B
- Mediates the upregulation of GCS expression in response to
- Oxidant stress,
- Inflammatory cytokines,
- Buthionine sulfoximine-induced GSH depletion [1]
Sulfur-containing amino acids
- As well as glutamate (glutamine or BCAAs) and glycine (or serine)
- Is critical for the maximization of GSH synthesis [1]
P.o. / i.v. suplementy
- Cystine,
- N-acetyl-cysteine
- L-2-oxothiazolidine-4-carboxylate
- Increasing the supply of cysteine or its precursors
