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.