Abstract
Photocarcinogenesis and photoaging are established consequences of chronic exposure of human skin to solar irradiation. Accumulating evidence supports a causative involvement of UVA irradiation in skin photo-damage. UVA photodamage has been attributed to photosensitization by endogenous skin chromophores leading to the formation of reactive oxygen species and organic free radicals as key mediators of cellular photooxidative stress. In this study, 3-hydroxypyridine derivatives contained in human skin have been identified as a novel class of potential endogenous photosensitizers. A structure-activity relationship study of skin cell photosensitization by endogenous pyridinium derivatives (pyridinoline, desmosine, pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5'-phosphate) and various synthetic hydroxypyridine isomers identified 3-hydroxypyridine and N-alkyl-3-hydroxypyridinium cation as minimum phototoxic chromophores sufficient to effect skin cell sensitization toward UVB and UVA, respectively. Photosensitization of cultured human skin keratinocytes (HaCaT) and fibroblasts (CF3) by endogenous and synthetic 3-hydroxypyridine derivatives led to a dose-dependent inhibition of proliferation, cell cycle arrest in G2/M, and induction of apoptosis, all of which were reversible by thiol antioxidant intervention. Enhancement of UVA-induced intracellular peroxide formation and p38 mitogen-activated protein kinase-dependent stress signaling suggest a photooxidative mechanism of skin cell photosensitization by 3-hydroxypyridine derivatives. 3-hydroxypyridine derivatives were potent photosensitizers of macromolecular damage, effecting protein (RNase A) photocross-linking and peptide (melittin) photooxidation with incorporation of molecular oxygen. Based on these results, we conclude that 3-hydroxypyridine derivatives comprising a wide range of skin biomolecules, such as enzymatic collagen cross-links, B6 vitamers, and probably advanced glycation end products in chronologically aged skin constitute a novel class of UVA photosensitizers, capable of skin photooxidative damage.
Highlights
Most of the solar UV energy incident on human skin is in the deeply penetrating UVA region (Ͼ95% from 320 to 400 nm)
3-hydroxypyridine derivatives contained in human skin have been identified as a novel class of potential endogenous photosensitizers
To examine the structural requirements for pyridinoline phototoxicity, we measured the sensitized inhibition of proliferation in cultured human fibroblasts (CF3) after cells were exposed to UVA irradiation (3.3 J/cm2) in the presence or absence of 500 M pyridinoline or desmosine (DES; see Fig. 1), a structurally related pyridinium cross-link extracted from elastin
Summary
Most of the solar UV energy incident on human skin is in the deeply penetrating UVA region (Ͼ95% from 320 to 400 nm). The formation of ROS as mediators of photooxidative stress in UV-irradiated skin seems to be dependent on non-DNA chromophores acting as endogenous photosensitizers [2, 3, 8]. Based on our previous identification of the collagen-derived pyridinium cross-link pyridinoline as a candidate photosensitizer contained in ECM proteins [17], a detailed structureactivity relationship study was undertaken to identify the minimum phototoxic chromophore contained in pyridinoline and various other pyridinium compounds from human skin. Photosensitization by Endogenous 3-HP Chromophores present evidence that 3-hydroxypyridine derivatives comprising a wide range of skin biomolecules, such as enzymatic collagen cross-links, B6 vitamers, and various advanced glycation end products, act as endogenous UVA photosensitizers
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