Endogenous UVA-photosensitizers: mediators of skin photodamage and novel targets for skin photoprotection

Abstract

Endogenous chromophores in human skin serve as photosensitizers involved in skin photocarcinogenesis and photoaging. Absorption of solar photons, particularly in the UVA region, induces the formation of photoexcited states of skin photosensitizers with subsequent generation of reactive oxygen species (ROS), organic free radicals and other toxic photoproducts that mediate skin photooxidative stress. The complexity of endogenous skin photosensitizers with regard to molecular structure, pathways of formation, mechanisms of action, and the diversity of relevant skin targets has hampered progress in this area of photobiology and most likely contributed to an underestimation of the importance of endogenous sensitizers in skin photodamage. Recently, UVA-fluorophores in extracellular matrix proteins formed posttranslationally as a consequence of enzymatic maturation or spontaneous chemical damage during chronological and actinic aging have been identified as an abundant source of light-driven ROS formation in skin upstream of photooxidative cellular stress. Importantly, sensitized skin cell photodamage by this bystander mechanism occurs after photoexcitation of sensitizers contained in skin structural proteins without direct cellular photon absorption thereby enhancing the potency and range of phototoxic UVA action in deeper layers of skin. The causative role of photoexcited states in skin photodamage suggests that direct molecular antagonism of photosensitization reactions using physical quenchers of photoexcited states offers a novel chemopreventive opportunity for skin photoprotection.

UVA radiation causes DNA strand breaks, chromosomal aberrations and tumorigenic transformation in HaCaT skin keratinocytes

“…The action of UVA is thought to be indirect by activating cellular chromophores and inducing photooxidative cellular stress (Wondrak et al, 2006). The thereby generated reactive oxygen species (ROS) can modify guanine to 8-oxo-7,8-dihydro-7 0 -deoxyguanosine (8-oxo-guanine) resulting in transversion mutations by changing guanine to thymine during replication (Cadet et al, 2005)-now considered as UVA signature mutations.…”

Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

“…This oxidative stress can occur through multiple mechanisms (reviewed in 79 ). However, a key mechanism occurs through photon absorption by endogenous, non-DNA chromophores, that then act as photosensitizers (S*, figure 1) that initiate ROS production 80 . Like UVA, UVB is also able to induce photo-oxidation through similar mechanisms.…”

“…Like UVA, UVB is also able to induce photo-oxidation through similar mechanisms. However, unlike UVA, UVB is also directly absorbed by DNA (λmax=260 nm), resulting in direct photoexcitation, molecular rearrangement, and genotoxicity 80 . Because of their much lower absorption maxima, polyunsaturated fatty acids do not absorb either UVA or UVB, thus they do not undergo direct photochemical reactions.…”

“…Because of their much lower absorption maxima, polyunsaturated fatty acids do not absorb either UVA or UVB, thus they do not undergo direct photochemical reactions. UVR mediated changes to phospholipids is therefore thought to occur as a result of photo-oxidation reactions 80 . Recent studies by photobiologists indicate that UVB generates ROS through a series of sequential steps involving: EGFR activation, ROS generation by cytosolic NADPH oxidase, ras/ERK & p38MAPK activation, p53 activation, and finally apoptotic signaling leading to mitochondrial ROS generation [81][82][83][84][85][86][87][88] .…”

Photoprotection of natural flavonoids

“…UVA radiation, known as aging rays, represents more than ninety percent of UV radiation that reaches the Earth's surface (Svobodová et al, 2003). It can penetrate deeper into the epidermis and dermis of the skin (around 1 mm) and advance the generation of reactive oxygen species (ROS) (Wondrak et al, 2006). Compared to UVB, UVA is about 1000 times more .…”