Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium
Open accessAbstract
A2E, an important constituent of lipofuscin in human retinal pigment epithelium (RPE), is thought to mediate light-induced oxidative damage associated with aging and other ocular disorders. Ocular carotenoids in overlying retinal tissues were measured by HPLC and mass spectrometry and were correlated with levels of RPE A2E. We observed a statistically significant increase in total A2E levels in human RPE/choroid with age, and A2E levels in macular regions were approximately 1/3 lower than in peripheral retinal regions of the same size. There was a statistically significant inverse correlation between peripheral retina carotenoids and peripheral RPE/choroid A2E. Prospective carotenoid supplementation studies in Japanese quail demonstrated nearly complete inhibition of A2E formation and oxidation. These findings support current recommendations to increase dietary intake of xanthophyll carotenoids in individuals at risk for macular degeneration and highlight a new potential mechanism for their protective effects-inhibition of A2E formation and oxidation in the eye.
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In the human eye, lipofuscin fluorescence does not reliably indicate A2E levels.
“These findings are in agreement with the data obtained from the tissue punch study (Bhosale et al., 2009), and demonstrate that lipofuscin fluorescence is not an adequate monitor of A2E in the human eye.”
From New insights into retinoid metabolism and cycling within the retina (2013) · cites this paper as Bhosale et al., 2009
The Discussion (page unavailable) says noninvasive quantitative A2E measurements in humans are difficult to perform reliably. The tissue-punch Results (page unavailable) quantify A2E by HPLC, but the paper does not compare those measurements with lipofuscin fluorescence or establish that fluorescence is an inadequate monitor of A2E. (LLM, conf=0.78)
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“our laboratory, typical extraction efficiencies from biological samples are >95%, and HPLC reproducibility with external standardization is 65%.(34,35)”
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“The A2E quantitation was calculated by using the A2E standard curve and normalized to protein level (Bhosale et al. 2009).”
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BackgroundEndogenous Fluorophores Enable Two-Photon Imaging of the Primate Eye
Palczewska, G., Golczak, M., Williams, D. R., Hunter, J. J., & Palczewski, K. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-14395 · Cited by 33 · see citing works
Yoon, S.-M., Lee, B.-L., Guo, Y.-R., & Choung, S. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-015-0683-7 · Cited by 33 · see citing works
“For A2E quantitation, an external standard of A2E was used (Bhosale et al. 2009).”
MethodMacular Pigment and Visual Performance in Low-Light Conditions
Stringham, J. M., Garcia, P. V., Smith, P. A., Hiers, P. L., McLin, L. N., KUYK, T. K., & Foutch, B. K. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15716 · Cited by 32 · see citing works
“activity of A2E, itself the product of oxidative stress, and a potent visual cycle inhibitor.(55) At the level of perception, a more efficient visual cycle could ultimately manifest as”
BackgroundToomey, M. B., & McGraw, K. J. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.06.033 · Cited by 29 · see citing works
Feldman, T. B., Dontsov, A. E., Yakovleva, M. A., & Оstrovsky, М. А. (2022) · Biophysical Reviews · doi:10.1007/s12551-022-00989-9 · Cited by 29 · see citing works
“The RPE cells from donors older than 50 years have significantly higher concentration of A2E (2–3 times more) compared to young donors (Bhosale et al. 2009).”
BackgroundAdler, L., Boyer, N. P., Anderson, D. M., Spraggins, J. M., Schey, K. L., Hanneken, A. M., Ablonczy, Z., Crouch, R. K., & Koutalos, Y. (2015) · Photochemical & Photobiological Sciences · doi:10.1039/c5pp00156k · Cited by 28 · see citing works
A2E and lipofuscin distributions in macaque retinal pigment epithelium are similar to human
Pallitto, P. M., Ablonczy, Z., Jones, E. E., Drake, R. R., Koutalos, Y., Crouch, R. K., Donello, J. E., & Herrmann, J. E. (2015) · Photochemical & Photobiological Sciences · doi:10.1039/c5pp00170f · Cited by 27 · see citing works
Bowrey, H. E., Anderson, D. M., Pallitto, P. M., Gutierrez, D. B., Fan, J., Crouch, R. K., Schey, K. L., & Ablonczy, Z. (2015) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201500103 · Cited by 27 · see citing works
“Extracted material from 8 mm macular and peripheral retina and RPE tissue punches provided evidence that bisretinoids are depleted in the macular area of the RPE, while carotenoids are abundant in macula retina [34].”
BackgroundRetinal Pigment Epithelium Pigment Granules: Norms, Age Relations and Pathology
Dontsov, A. E., & Оstrovsky, М. А. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073609 · Cited by 27 · see citing works
“A2E may accumulate in RPE cells during aging [71] and act as an auto-oxidant by increasing oxidative stress [72] through the photogeneration of ROS such as superoxide radicals [73–75] and singlet oxygen [73,76].”
BackgroundOxidative stability of yogurt with added lutein dye
Domingos, L. D., Xavier, A. A. O., Mercadante, A. Z., Petenate, A. J., Jorge, R. A., & Viotto, W. H. (2013) · Journal of Dairy Science · doi:10.3168/jds.2013-6971 · Cited by 24 · see citing works
Human Foveal Cone and RPE Cell Topographies and Their Correspondence With Foveal Shape
Baraas, R. C., Pedersen, H. R., Kenneth Knoblauch, B., & Gilson, S. J. (2022) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.63.2.8 · Cited by 23 · see citing works
“25 26 This lends support to the suggestion that the development and maturation of the RPE cell sheet could contribute to formation and maintenance of foveal shape and the considerable differences in peak cone density and topographies of foveal cones as observed in both ex vivo 38 and in vivo 52…”
Mass spectrometry provides accurate and sensitive quantitation of A2E
Gutierrez, D. B., Blakeley, L. R., Goletz, P. W., Schey, K. L., Hanneken, A. M., Koutalos, Y., Crouch, R. K., & Ablonczy, Z. (2010) · Photochemical & Photobiological Sciences · doi:10.1039/c0pp00230e · Cited by 23 · see citing works
Fontaine, V. K., Monteiro, E., Brazhnikova, E., Lesage, L., Balducci, C., Guibout, L., Feraille, L., Elena, P.-P., Sahel, J., Veillet, S., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0167793 · Cited by 23 · see citing works
“Lutein and zeaxanthin, which are naturally present in the human macula, decreased A2E levels in RPE of Japanese quails after 16 weeks of supplementation [36].”
BackgroundCurcio, C. A., Messinger, J. D., Berlin, A., Sloan, K. R., McLeod, D. S., Edwards, M. M., Bijon, J., & Freund, K. B. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.1.49 · Cited by 22 · see citing works
Dry Age-Related Macular Degeneration Pharmacology
Wright, C. B., & Ambati, J. (2016) · Handbook of experimental pharmacology · doi:10.1007/164_2016_36 · Cited by 22 · see citing works
“2000), but later work found A2E primarily accumulated in the periphery of AMD eyes (Bhosale et al. 2009), not in the macula.”
BackgroundElevated Fundus Autofluorescence in Monkeys Deficient in Lutein, Zeaxanthin, and Omega-3 Fatty Acids
McGill, T. J., Renner, L. M., & Neuringer, M. D. (2016) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-18596 · Cited by 21 · see citing works
“Dietary deficiencies of antioxidants, including vitamin E, have been shown to increase lipofuscin accumulation,58–62 as has treatment with prooxidants, such as iron.63 Conversely, in RPE cells in vitro, the addition of vitamin E or L/Z decreases lipofuscin formation.64,65 Bhosale et al.66 showed in peripheral human RP…”
BackgroundKotnala, A., Senthilkumari, S., Gong, W., Stewart, T. G., Curcio, C. A., Halder, N., Singh, S. B., Kumar, A., & Velpandian, T. (2022) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.63.6.6 · Cited by 17 · see citing works
“27 They divided eye donors into 2 groups: < 50 years ( n = 22) and > 50 years ( n = 31) and observed an increase in A2E in the periphery, compared to the macula, by 3.9 and 3.39-fold using LC-ESI-MS/MS. 27 Ablonczy et al. further validated the observation of more A2E detected in peripheral retina…”
InfluentialProtective effect of lutein on oxidative stress damage caused by acute PM2.5 exposure in rats
Chen, X., Chen, Y., Chen, Y., Wang, X., & He, M. T. (2020) · Annals of Palliative Medicine · doi:10.21037/apm-20-1138 · Cited by 17 · see citing works
“Previous lutein studies have mainly focused on its protective effect on the retina (8,9).”
BackgroundSmith, R. T., Bernstein, P. S., & Curcio, C. A. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-12798 · Cited by 17 · see citing works
Self-citationGrey, A. C. (2016) · International Journal of Mass Spectrometry · doi:10.1016/j.ijms.2016.02.017 · Cited by 15 · see citing works
Food for Eye Health: Carotenoids and Omega-3 Fatty Acids
Chiu, H., Shen, Y., Venkatakrishnan, K., & Wang, C. (2018) · Elsevier eBooks · doi:10.1016/b978-0-08-100596-5.21740-x · Cited by 13 · see citing works
Macular Pigment Carotenoids and Bisretinoid A2E
Arunkumar, R., & Bernstein, P. S. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-27681-1_3 · Cited by 10 · see citing works
Self-citationPradhan, S. P., Padhi, S., Dash, M., Heena, Mittu, B., & Behera, A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-89779-2.00006-5 · Cited by 10 · see citing works
Extraction, detection, and imaging of the macular carotenoids
Li, B., Gorusupudi, A., Arunkumar, R., & Bernstein, P. S. (2022) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2022.05.001 · Cited by 8 · see citing works
Self-citationRod-Mediated Dark Adaptation and Macular Pigment Optical Density in Older Adults with Normal Maculas
Zarubina, A. V., Huisingh, C., Clark, M. E., Sloan, K. R., McGwin, G., Crosson, J. N., Curcio, C. A., & Owsley, C. J. (2018) · Current Eye Research · doi:10.1080/02713683.2018.1460380 · Cited by 8 · see citing works
“with new technologies that assay the composition of many tissue layers simultaneously, in individual eyes.(56,57) New data on MP biology and retinal imaging technologies”
MethodFontaine, V. K., Balducci, C., Dinan, L. N., Monteiro, E., Boumedine, T., Fournié, M., Nguyen, V., Guibout, L., Clatot, J., Latil, M., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065296 · Cited by 7 · see citing works
“We also demonstrated the neuroprotective effects and the preservation of visual function, especially of rod photoreceptors by BIO201 in various in vivo animal models of AMD [4,7] and as previously demonstrated for retinal carotenoids such as lutein, norbixin reduced the accumulation of A2E [4,7,25].”
BackgroundWashington, I., & Saad, L. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-17121-0_46 · Cited by 7 · see citing works
Petrukhin, K. E. (2020) · Topics in medicinal chemistry · doi:10.1007/7355_2020_105 · Cited by 6 · see citing works
Hussnain, S. A., Dolz‐Marco, R., Dunaief, J. L., Curcio, C. A., & Freund, K. B. (2018) · Retina · doi:10.1097/iae.0000000000002367 · Cited by 6 · see citing works
Toomey, M. B., & McGraw, K. J. (2016) · Avian Research · doi:10.1186/s40657-016-0041-6 · Cited by 5 · see citing works
“Increased carotenoid accumulation in the avian retina, through dietary supplementation, has been shown to reduce light-induced photoreceptor death and the formation of N-retinyl-N-retetinylidene ethanolamin (A2E), a marker of light-induced oxidative damage (Thomson et al. 2002a, b; Bhosale et al. 2009).”
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Kotnala, A., Senthilkumari, S., Halder, N., Kumar, A., & Velpandian, T. (2017) · Journal of Chromatography B · doi:10.1016/j.jchromb.2017.11.021 · Cited by 2 · see citing works
Nutrition and optometric practice: Functional roles of lutein and zeaxanthin in visual performance
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Age-Related Macular Degeneration and Vision Impairment
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Dry Age-Related Macular Degeneration –Prevention with A Plant-Based Diet
Strombom, A. J. (2021) · JOJ Ophthalmology · doi:10.19080/jojo.2021.09.555752
“of by-products of vitamin A metabolism and lipid peroxidation [47-49].”
BackgroundMuth, D. R., Venkataraman, A. P., Domínguez‐Vicent, A., Petrovski, G., Williams, P. A., Quérat, L., Locri, F., Zweifel, S. A., & Kvanta, A. (2026) · Acta Ophthalmologica · doi:10.1111/aos.70229
- Authors
- Bhosale, P., Serban, B., & Bernstein, P. S.
- Affiliations
- University of Utah (US)
- Corresponding author
- Bernstein, Paul S.
- ORCID
- Bernstein, Paul S.
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 483
- Issue
- 2
- Pages
- 175-181
- ISSN
- 0003-9861 (ISSN-L)
- PMC
- PMC2683766
- OpenAlex
- W1970986305
- Cited by
- 85
- References
- 38
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 9 · 2015: 11 · 2014: 4 · 2013: 8 · 2012: 6
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Research to Prevent Blindness
- National Institute for Health and Care Research
- National Institutes of Health
- National Eye Institute (EY-11600, R29EY011600, R01EY011600)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- A2E, retinal carotenoids, retinal pigment epithelium, lipofuscin, xanthophylls, macular degeneration, oxidative damage, aging, carotenoid supplementation, Japanese quail, macula, choroid
- MeSH terms
- Animals, Carotenoids, Chromatography, High Pressure Liquid, Coturnix, Humans, Pyridinium Compounds, Retinoids, Spectrometry, Mass, Electrospray Ionization, Retinal Pigment Epithelium
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