The malondialdehyde-derived fluorophore DHP-lysine is a potent sensitizer of UVA-induced photooxidative stress in human skin cells.

Abstract

Light-driven electron and energy transfer involving non-DNA skin chromophores as endogenous photosensitizers induces oxidative stress in UVA-exposed human skin, a process relevant to photoaging and photocarcinogenesis. Malondialdehyde is an electrophilic dicarbonyl-species derived from membrane lipid peroxidation. Here, we present experimental evidence suggesting that the malondialdehyde-derived protein epitope dihydropyridine (DHP)-lysine is a potent endogenous UVA-photosensitizer of human skin cells. Immunohistochemical analysis revealed the abundant occurrence of malondialdehyde-derived and DHP-lysine epitopes in human skin. Using the chemically protected dihydropyridine-derivative (2S)-Boc-2-amino-6-(3,5-diformyl-4-methyl-4H-pyridin-1-yl)-hexanoic acid-t-butylester as a model of peptide-bound DHP-lysine, photodynamic inhibition of proliferation and induction of cell death were observed in human skin Hs27 fibroblasts as well as primary and HaCaT keratinocytes exposed to the combined action of UVA and DHP-lysine. DHP-lysine photosensitization induced intracellular oxidative stress, p38 MAPkinase activation, and upregulation of heme oxygenase-1 expression. Consistent with UVA-driven ROS formation from DHP-lysine, formation of superoxide, hydrogen peroxide, and singlet oxygen was detected in chemical assays, but little protection was achieved using SOD or catalase during cellular photosensitization. In contrast, inclusion of NaN(3) completely abolished DHP-photosensitization. Taken together, these data demonstrate photodynamic activity of DHP-lysine and support the hypothesis that malondialdehyde-derived protein-epitopes may function as endogenous sensitizers of UVA-induced oxidative stress in human skin.

• Authors: Sarah D Lamore, Sara Azimian, David Horn, Bobbi L Anglin, Koji Uchida, Christopher M Cabello, Georg T Wondrak
• Journal: Journal of photochemistry and photobiology. B, Biology (J Photochem Photobiol B) Vol. 101 Issue 3 Pg. 251-64 (Dec 02 2010) ISSN: 1873-2682 [Electronic] Switzerland
• PMID: 20724175 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Photosensitizing Agents
• Pyridines
• Reactive Oxygen Species
• Malondialdehyde
• Sodium Azide
• Catalase
• Heme Oxygenase-1
• Superoxide Dismutase
• p38 Mitogen-Activated Protein Kinases
• Lysine

Topics

• Apoptosis
• Catalase (metabolism)
• Fibroblasts (drug effects, metabolism, radiation effects)
• Heme Oxygenase-1 (metabolism)
• Humans
• Keratinocytes (drug effects, metabolism, radiation effects)
• Lysine (analogs & derivatives, chemistry)
• Malondialdehyde (chemistry)
• Oxidative Stress
• Photosensitizing Agents (chemistry)
• Pyridines (chemistry)
• Reactive Oxygen Species (metabolism)
• Skin (drug effects, radiation effects)
• Sodium Azide (pharmacology)
• Superoxide Dismutase (metabolism)
• Ultraviolet Rays
• p38 Mitogen-Activated Protein Kinases (metabolism)