Zinc and the AMD Disease Process

Zinc is concentrated in the choriocapillaries, retinal pigment epithelium (RPE) and retina. Long term supplementation with zinc, either alone or combined with antioxidants, was shown to slow AMD progression in the AREDS trial. Not much is known, however, about the effects elicited by this mineral.

Recent results from an ancillary study to AREDS suggest one way that zinc may help protect against AMD. Zinc appears to improve the transport and use of cysteine - a sulfur containing amino acid and rate limiting factor in the manufacture of glutathione, the major antioxidant within cells.

Glutathione helps inactivate the reactive oxygen species hydrogen peroxide by reducing it to water. In this process, the reduced form of glutathione (GSH) is oxidized to produce GSSG. Like glutathione, cysteine also contains a thiol or sulphhydryl group. Thiol groups can undergo oxidation/reduction (redox) reactions; when cysteine (Cys) is oxidized it forms cystine (CySS). Due to its ability to undergo redox reactions, cysteine has antioxidant properties.

Studies have shown that plasma levels of cysteine and glutathione become more oxidized with age, age-related diseases, and oxidative stress. Plasma levels of the reduced and oxidized forms of these metabolites are thought to be a reliable marker for oxidative stress and antioxidant defenses.

Methods

Plasma samples were obtained from AREDS participants at the Emory and Wilmer Eye Centers sites. At both study sites, blood specimens were obtained at two time points, an average of 1.7 and 6.7 years after enrollment. For this study, the four AREDS treatment groups were combined into two groups: zinc supplementation and no zinc. Plasma was analyzed for the reduced and oxidized forms of glutathione and cysteine (GSH / GSSG and cysteine / cystine), and their redox status.

Results

To control for factors that may have an effect on the plasma levels of these metabolites, demographic characteristics were compared. There were no significant differences in these characteristics between subjects receiving zinc or no zinc at either blood draw.

At the first blood draw (20 months), most subjects had already entered the study and were receiving zinc or placebo. No differences were seen in any of the thiols, disulfides or redox states between the two groups.

At the second blood draw (80 months), a significant decrease in plasma levels of oxidized cysteine (cystine, CySS) was found in the group receiving zinc compared to the non-zinc group (Fig. 1 below).

FIGURE 1. Long-term zinc supplementation resulted in lower plasma cystine (CySS) in the AREDS patients. Plasma CySS was measured in AMD patients before and after five years of zinc supplementation. Subjects who had received zinc had significantly lower CySS than their baseline values (P= .05). Additionally, at draw 2, plasma CySS was significantly higher in the no zinc group compared to the zinc group (P = .02).

Discussion

How might the lower plasma levels of oxidized cysteine (CySS) affect retinal cells? Whether the magnitude of change found in this study affects RPE function remains to be determined. However, earlier studies found that exposing cultured human RPE cells to a more oxidized "cystine environment" makes them more susceptible to apoptosis or programmed death.

Reference

Moriarty-Craige BS, et al. Effects of long-term zinc supplementation on plasma thiol metabolites and redox status in patients with age-related macular degeneration. Am J Ophthalmol 143:206-11, 2007.