## 4 Skin Biology, Vitamin D Synthesis, and Its Impacting Factors
### Synthesis and Metabolism of Vitamin D in Human Skin
Furthermore, younger age, darker skin type, not using vitamin D supplementation, not consuming oily fish, and living in specific low-UV regions are all predicting factors of vitamin D deficiency, poor myoskeletal health, and chronic health issues [126]. Such observation comes in accordance with research studies highlighting that the risk of rickets and osteomalacia is higher in completely clothed Bedouin peopleunder similar sunshine conditions than in less covered cultures, suggesting that clothing based either on personal preferences or religious practices and sunscreens may limit D\({}_{3}\) production. Conflicting studies, however, proved that the use of sunscreen during summer allows sufficient sunlight to be received, enables vitamin D, and does not interfere with vitamin D deficiency [127,128]. The skin produces vitamin D\({}_{3}\) in a safe and controlled manner thanks to photoconversion procedures and environmental influences [129]. Of note, ozone has an excellent function in mitigating hazardous UV\({}_{\text{C}}\) rays that pass through the stratosphere, and hence, preserves skin health [130]. Following its production, the metabolism of vitamin D\({}_{3}\) is a procedure first conducted in the liver and then in the kidneys. Vitamins deriving especially from food bind to the _VDR_, with this complex reaching the liver and being converted to 25(OH)D\({}_{3}\). This compound, as it reaches the kidney, is then enzymatically converted by 25(OH)D\({}_{3}\)-1\(\alpha\)-hydroxylase (CYP27B1) and several other cofactors like nicotinamide adenine dinucleotide phosphate (NADPH), magnesium, and interaction with other degrading enzymes of vitamin D metabolites, like CYP3A4, to two distinct bioactives. More specifically, through a hydroxylation in the 1\(\alpha\) (A ring) position, 25(OH)D\({}_{3}\) is converted to 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) and through the hydroxylation in the 24 th position, 25(OH)D\({}_{3}\) is directly converted to 24,25-dihydroxyvitamin D\({}_{3}\) (24,25(OH)\({}_{2}\)D\({}_{3}\)). The first conversion leads to increased PTH and fibroblast growth factor-23 (FGF-23) levels and decreased phosphorus (P) (phosphate excretion by the kidneys) and Ca levels (calcium resorption from bones), while the second conversion, in contrast, leads to elevated P and Ca (due to renal reabsorption of phosphate) levels (Figure 5) [30]. Ultimately, 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) promotes calcium and phosphate absorption, while 24,25(OH)\({}_{2}\)D\({}_{3}\) inhibits excessive Ca absorption, preserving balance [30]. However, excessive 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) may lead to conditions like hypercalcemia and hyperphosphatemia, contributing to complications such as vascular classification, skeletal anomalies, and renal calculi [131,132]. Furthermore, in CKD patients, impaired 1\(\alpha\)-hydrolase activity results in decreased 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) levels, leading to secondary hy  
Figure 5: The production of vitamin D\({}_{3}\) from 7–DHC in the skin epidermis. (Reproduced from [30], while the structures were obtained from PubChem ([[https://pubchem.ncbi.nlm.nih.gov/](https://pubchem.ncbi.nlm.nih.gov/)]([https://pubchem.ncbi.nlm.nih.gov/](https://pubchem.ncbi.nlm.nih.gov/)) (accessed on 29 December 2024)), and Moliview ([[https://molview.org/](https://molview.org/)]([https://molview.org/](https://molview.org/)) (accessed on 29 December 2024)). perparathyroidismroidism and bone mineral disorders [30,103]. On this note, a deficiency in 25-hydroxylase, otherwise CYP2R1 deficiency, induces vitamin D-dependent rickets type 1B [133,134]; CYP27B1 mutations are associated with vitamin D-dependent rickets type 1A [133,135], and polymorphisms in CYP24A1 may cause hypercalcemia [133,136]. Besides producing vitamin D\({}_{3}\), keratinocytes also convert it into its active form, 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\), through the enzymes vitamin D-25 hydroxylase CYP27A and CYP27B1.