Original article
Effects of Long-term Zinc Supplementation on Plasma Thiol Metabolites and Redox Status in Patients With Age-related Macular Degeneration

https://doi.org/10.1016/j.ajo.2006.09.056Get rights and content

Purpose

To determine the effects of zinc supplementation on plasma thiol metabolites and their redox status in a cohort of patients with age-related macular degeneration (AMD).

Design

Randomized clinical trial that evaluated the effects of high doses of zinc and antioxidants on plasma biomarkers of oxidative stress.

Methods

This was an ancillary study of the Age-Related Eye Disease Study (AREDS). Subjects with AMD were randomized to one of four treatment groups: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg), (2) zinc (80 mg zinc oxide, 2 mg cupric oxide), (3) antioxidants plus zinc, or (4) placebo. At 20 and 80 months after randomization, blood specimens were collected and analyzed for glutathione (GSH), oxidized glutathione (GSSG), cysteine (Cys), and cystine (CySS).

Results

Although zinc supplementation had no apparent effect on plasma thiol/disulfide redox status at the first blood draw, the group of patients receiving zinc supplementation at the second blood draw had significantly less CySS compared with those not receiving zinc (54.9 vs 64.1 μM; P = .01). There was a time-dependent oxidation of the plasma GHS pool and was not affected by zinc supplementation.

Conclusions

Because increased CySS level is associated with aging, oxidative stress, and age-related diseases, the apparent prevention of increased CySS by zinc supplementation warrants additional investigation.

Section snippets

Methods

We obtained plasma samples from subjects who had been enrolled in the AREDS multicenter clinical trial.8 This trial was designed to evaluate the effects of antioxidant and/or zinc supplementation on the progression of AMD in a cohort of individuals between age 55 and 80. All participants at the Emory and Wilmer Eye Centers who could be scheduled for blood collection during regular visits were included. Participants with AMD were randomly assigned to one of four treatment groups: (1)

Subject demographic characteristics

To control for other factors (age, smoking, obesity, and diabetes) that may have an effect on the plasma thiols, we examined the average age of the patients, smoking habits, body mass index (BMI), and the presence of diabetes. In this study, a total of 312 AMD subjects were identified for the first blood draw, with 112 from Emory and 200 from Johns Hopkins. There were 82 AMD subjects for the second blood draw, with 51 from Emory and 31 from Johns Hopkins. There were no significant differences

Discussion

AMD is the leading cause of blindness in the elderly, affecting seven million Americans, 1.75 million of whom have more advanced disease associated with severe vision loss. It is estimated that the number of people with advanced AMD will double by the year 2020.22 Following AREDS, zinc and antioxidant supplementation became the only accepted preventive measure for atrophic or “dry” AMD. Despite the widespread intake of zinc, little is known about the biochemical effects elicited by zinc.

This

Paul Sternberg, Jr, MD, is the G. W. Hale Professor and Chair of the Vanderbilt Eye Institute, Nashville, Tennessee. He is a graduate of Harvard University, Boston, Massachusetts and the University of Chicago, Chicago, Illinois, and received his Ophthalmology training at Wilmer Ophthalmological Institute, Baltimore, Maryland, and Duke Univesity, Durham, North Carolina. His laboratory research interests focus on the pathogenesis of age-related macular degeneration. Dr Sternberg, Jr, team

References (28)

Cited by (29)

  • Impact of sex, age and diet on the cysteine/cystine and glutathione/glutathione disulfide plasma redox couples in mice

    2020, Journal of Nutritional Biochemistry
    Citation Excerpt :

    Furthermore, some disease processes are themselves associated with changes in plasma redox potentials [24–27]. Intriguingly, redox potentials can be restored by simply supplementing the diet with SAA [16,19,23,28], exercising [18], or taking zinc supplements [29]. Changes in plasma redox potentials have been reported in a small number of animal models, including rats and non-human primates [30–34].

  • The short-term effects of antioxidant and zinc supplements on oxidative stress biomarker levels in plasma: A pilot investigation

    2012, American Journal of Ophthalmology
    Citation Excerpt :

    Our previous work has indicated that thiol redox status can be modified with antioxidant and zinc therapy. Previously, we have shown that the Cys/CySS pool is responsive to long-term treatment with antioxidants9 and zinc.10 Additionally, human RPE cells treated with zinc demonstrated increased GSH levels.25

  • Plasma biomarkers of oxidative stress and genetic variants in age-related macular degeneration

    2012, American Journal of Ophthalmology
    Citation Excerpt :

    In conclusion, it seems that these biomarkers may be associated more closely with AMD risk factors than with AMD itself. We previously reported that long-term zinc supplementation decreased plasma CySS levels in a subset of the AREDS study population.60 The results of this study suggest that the positive response of AMD patients to zinc treatment may be the result of offsetting increased oxidative stress caused by aging.

  • Cysteine/cystine redox signaling in cardiovascular disease

    2011, Free Radical Biology and Medicine
    Citation Excerpt :

    Other studies show that zinc, dietary sulfur amino acid intake level, and acetaminophen use can affect plasma Eh in humans. The effects of zinc (Zn) supplementation on plasma thiol metabolites and their redox status were studied in a cohort of patients with age-related macular degeneration [32]. Results showed that patients receiving Zn supplementation for 5 years had significantly less plasma CySS compared with those not receiving zinc [32].

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Paul Sternberg, Jr, MD, is the G. W. Hale Professor and Chair of the Vanderbilt Eye Institute, Nashville, Tennessee. He is a graduate of Harvard University, Boston, Massachusetts and the University of Chicago, Chicago, Illinois, and received his Ophthalmology training at Wilmer Ophthalmological Institute, Baltimore, Maryland, and Duke Univesity, Durham, North Carolina. His laboratory research interests focus on the pathogenesis of age-related macular degeneration. Dr Sternberg, Jr, team performed the ancillary studies to the AREDS, using plasma biomarkers of oxidative stress to monitor the therapeutic effects of supplementation with zinc and antioxidant vitamins.

Dean P. Jones, PhD, is a Professor of Medicine and Director of the Clinical Biomarkers Laboratory at Emory University. He received his PhD from Oregon Health Sciences University, Portland, Oregon, and postdoctoral training at Cornell University, Ithaca, New York. Dr Jones studies mechanisms of redox circuitry in mammalian cells. He has collaborated with a number of clinical investigators, including Dr Sternberg, on biomarker measurements in various human diseases, including age-related macular degeneration.

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