High levels of gamma-glutamyltransferase activity (GGT) in serum are commonly interpreted to indicate hepatocellular damage, oxidative stress and increased need for intracellular glutathione (GSH). The liver is the primary exporter of GSH and free GGT, and membrane bound GGT is essential for the indirect import of GSH by cells- especially neurons. Paradoxically, however, membrane bound GGT may result in the generation of reactive oxygen species, free radicals, and oxidative damage. Unique properties of the liposomal-GSH delivery system bypass the GGT paradox, and maximize clinical efforts to safely and effectively fulfill physiological demands for increased intracellular GSH.
Serum GGT has no known physiological function, but rather it serves as a biomarker; elevated levels may be associated with liver diseases, excessive alcohol consumption, enzyme-inducing drugs, chronic pancreatitis, diabetes, and cardiovascular disease. Results from the Framingham Offspring Study are suggestive that slightly elevated serum GGT may be an early predictor of MetS, CVD, heart failure and all-cause mortality. In contrast, GGT bound to cell membranes throughout the body has a key role in maintaining intracellular glutathione levels. Circulating GSH must be enzymatically broken down to its constitutive amino acids by GGT and dipeptidases prior to intracellular “resynthesis” of the tripeptide; no direct uptake of circulating native GSH occurs. Among its numerous important intracellular functions, quintessential GSH is required for detoxification of chemical and metal toxicants, and anti-oxidant protection against highly reactive peroxynitrite, superoxide, lipid peroxides, and hydrogen peroxide.
Conditions associated with abnormal levels of serum GGT are characterized by diminished GSH status and heightened production of reactive oxygen species (ROS) - not a good scenario. It is paradoxical that membrane bound GGT has been documented to increase oxidative stress, particularly in the presence of transition metals (e.g. iron, copper). Specifically, the product of GGT, cysteinylglycine, drives local production of ROS via reductive release of iron from transferrin. The free iron (or copper) initiates the local production of hydrogen peroxide, lipid peroxides and downstream oxygen radicals. The pro-oxidative effect of membrane-bound GGT is under investigation regarding a potentially causal relationship between functional polymorphisms in GGT1 (over expression), and predisposition for chronic pancreatitis and pancreatic cancer.
A hallmark study delineated the mechanisms by which a commercially available liposomal-GSH (L-GSH) preparation bypasses the GGT paradox, efficiently replenished intracellular GSH, and directly eliminated hydrogen peroxide. Utilizing an in vitro model of environmental Parkinson’s disease (GSH depleted, cultured mesencephalic neurons/glial cells), it was clearly demonstrated that the L-GSH was not a substrate for GGT, but it was taken up and hydrolyzed by endosomal and lysosomal processes prior to repletion of intracellular GSH via resynthesis of GSH. It was further demonstrated that the L-GSH, but not empty liposomes, protected dopaminergic neurons from paraquat/plus maneb (herbicide/fungicide), and the L-GSH quenched hydrogen peroxide in a dose dependent manner (non-enzymatically). The latter effect is attributable to the fact that hydrogen peroxide readily diffuses into liposomal vesicles.
Commonly encountered adverse health conditions are associated with diminished GSH status, including Metabolic syndrome, CVD, Parkinson’s disease, viral/mycobacterium infections, and exposures to environmental toxicants. GSH repletion efforts (e.g. cysteine, N-AC, GSH esters) may be associated with variable neurotoxic potential, and intravenously administered GSH has an impractically short half-life (14 minutes). Alternatively, an alcohol-free liposomal GSH product has been shown to ameliorate atherogenesis (animal model), improve GSH status in children with ASD, and mediate control of Mycobacterium tuberculosis infection in HIV-infected subjects. Importantly, L-GSH bypasses the pro-oxidative potential of membrane bound GGT, and has a remarkable safety profile. Intracellular GSH status can be conveniently assessed and monitored via RBC GSH testing.
