The reducing compound
glutathione (GSH) exists in an unusually high concentration in the lens where it functions as an essential
antioxidant vital for maintenance of the tissue's transparency. In conjunction with an active
glutathione redox cycle located in the lens epithelium and superficial cortex, GSH detoxifies potentially damaging
oxidants such as H2O2 and
dehydroascorbic acid. Recent studies have indicated an important
hydroxyl radical-scavenging function for GSH in lens epithelial cells, independent of the cells' ability to detoxify H2O2. Depletion of GSH or inhibition of the redox cycle allows low levels of
oxidant to damage lens epithelial targets such as Na/K-
ATPase, certain
cytoskeletal proteins and
proteins associated with normal membrane permeability. The level of GSH in the nucleus of the lens is relatively low, particularly in the aging lens, and exactly how the compound travels from the epithelium to the central region of the organ is not known. Recently, a cortical/nuclear barrier to GSH migration in older human
lenses was demonstrated by Sweeney et al. The relatively low ratio of GSH to
protein -SH in the nucleus of the lens, combined with low activity of the
glutathione redox cycle in this region, makes the nucleus especially vulnerable to oxidative stress, as has been demonstrated with use of in vivo experimental animal models such as hyperbaric
oxygen, UVA light and the
glutathione peroxidase knockout mouse. Effects observed in these models, which are currently being utilized to investigate the mechanism of formation of human senile nuclear
cataract, include an increase in lens nuclear
disulfide, damage to nuclear membranes and an increase in nuclear light scattering. A need exists for development of therapeutic agents to slow age-related loss of
antioxidant activity in the nucleus of the human lens to delay the onset of
cataract.