Page 33 - Read Online

Page 2 of 10 Philips et al. Plast Aesthet Res 2022;9:4 https://dx.doi.org/10.20517/2347-9264.2021.83

INTRODUCTION
Vitamin D (VD) is a prohormone involved in a broad range of functions in the organism that has been
[1]
[2]
shown to exert protective effects against several types of cancer and skin aging , among others. In the
human epidermis, exposure to sunlight - ultraviolet B radiation (UVB, 280-315 nm) - promotes the
transformation of 7-dehydrocholesterol to previtamin D , which undergoes thermal isomerization into
3
cholecalciferol, also known as vitamin D [Figure 1]. Cholecalciferol is then hydroxylated in the liver to 25-
3
hydroxycholecalciferol or calcidiol, and further hydroxylated in the kidney into 1,25-dihydroxyvitamin D
3
or calcitriol, which is the biologically active form of VD . Calcitriol, therefore, acts through an intracellular
[3]
receptor, vitamin D receptor (VDR), which is ubiquitously expressed in most nucleated cells . Calcitriol
[4]
[5]
exerts antiproliferative, antiangiogenic, pro-differentiating, and antiapoptotic effects .
Recent research has identified an alternative vitamin D activation pathway through CYP11A1 . CYP11A1-
[6-8]
mediated metabolism of vitamin D results in the production of 20-hydroxyvitamin D and its
hydroxymetabolites. These byproducts have antiproliferative, differentiative, and anti-inflammatory effects
[9]
in skin cells, comparable or greater than those of calcitriol . Additionally, these metabolites improve
different defense mechanisms against UVB-induced DNA damage and oxidative stress [9,10] . Alternative
nuclear receptors for vitamin D hydroxyderivaties have also been identified, such as retinoid-related orphan
receptor (ROR) alpha and ROR gamma [11-13] .

Both skin aging and cancer have been associated with increased cellular oxidative stress, the release of
inflammatory and angiogenic mediators, and abnormal extracellular matrix (ECM) remodeling, among
others [14-17] . Other non-classic effects of VD include cell growth suppression, apoptosis regulation,
modulation of immune responses, control of differentiation, or antioxidant effect, among others ,
[18]
suggesting that VD might be of potential relevance in skin aging and cancer.

OXIDATIVE DAMAGE
Cellular oxidative stress arises when the levels of reactive oxygen species (ROS), including hydroxyl radicals,
superoxide, or hydrogen peroxide, exceed the ability of endogenous antioxidants or antioxidant enzymes to
[19]
quench them . These antioxidant systems include glutathione, glutathione peroxidase, superoxide
dismutase, and catalase [20,21] . Oxidative damage occurs during the intrinsic cutaneous aging phenomenon,
and it is exacerbated by exposure of the skin to damaging physical or environmental pollutants such as
ultraviolet (UV) radiation, heavy metals, or benzene derivatives [22-26] . UVA radiation (315-400 nm) reaches
the dermis, causing DNA damage mainly through oxidative stress, whereas UVB (280-15 nm) reaches the
epidermis and causes direct DNA damage as well as oxidative stress-related DNA damage [20,21,23,24,27] . In
addition, exposure to pollutants also results in detrimental alterations through direct oxidative stress [25,26] .
Intrinsic skin aging is also associated with diminished levels of steroidal hormones, among others, thus,
[22]
resulting in the thinning and fine wrinkling of the skin . Additionally, ROS produced by extrinsic
damaging factors correlates with coarse wrinkling.

In relation to carcinogenesis, numerous studies have demonstrated that ROS are able to induce mutagenesis
through diverse mechanisms. In fact, nucleotides are highly susceptible to free radical damage, and their
oxidation promotes base mispairing, leading to mutagenesis . One of the best-characterized mutations
[28]
caused by ROS is the conversion of guanine into thymine, as a result of guanine oxidation at the eighth
position, resulting in 8-hydroxy-2’-deoxyguanine (8-OHdG) production . This last nucleotide base tends
[29]
to pair with adenine instead of cytosine, leading to mispairing and mutagenesis. These mutations have been
extensively found in different types of skin tumors . Furthermore, exposure to UV radiation has
[30]
mutagenic effects beyond the time of exposure due to ROS production, leading to the so-called dark-