Chapter 057. Photosensitivity and Other Reactions to Light (Part 3)

Vitamin D Photochemistry Cutaneous exposure to UV-B causes photolysis of epidermal 7dehydrocholesterol converting it to pre-vitamin D3, which then undergoes a temperature-dependent isomerization to form the stable hormone vitamin D3. This compound then diffuses to the dermal vasculature and circulates systemically where it is converted to the functional hormone 1,25-dihydroxyvitamin D3[1,25(OH)2D3]. Vitamin D metabolites from the circulation or those produced in the skin itself can augment epidermal differentiation signaling. Controversy exists regarding the importance of sun exposure in vitamin D homeostasis. At present, it is important to emphasize that the use of sunscreens does not substantially diminish vitamin D...
Nội dung trích xuất từ tài liệu:
Chapter 057. Photosensitivity and Other Reactions to Light (Part 3) Chapter 057. Photosensitivity and Other Reactions to Light (Part 3) Vitamin D Photochemistry Cutaneous exposure to UV-B causes photolysis of epidermal 7-dehydrocholesterol converting it to pre-vitamin D3, which then undergoes atemperature-dependent isomerization to form the stable hormone vitamin D3. Thiscompound then diffuses to the dermal vasculature and circulates systemicallywhere it is converted to the functional hormone 1,25-dihydroxyvitaminD3[1,25(OH)2D3]. Vitamin D metabolites from the circulation or those produced inthe skin itself can augment epidermal differentiation signaling. Controversy existsregarding the importance of sun exposure in vitamin D homeostasis. At present, itis important to emphasize that the use of sunscreens does not substantiallydiminish vitamin D levels. Since aging also substantially decreases the ability ofhuman skin to photocatalytically produce vitamin D3, the widespread use ofsunscreens that filter out UV-B has led to concern that vitamin D deficiency maybecome a significant clinical problem in the elderly. Chronic Effects of Sun Exposure: Nonmalignant The clinical features of photodamaged sun-exposed skin consist ofwrinkling, blotchiness, and telangiectasia and a roughened, irregular, weather-beaten leathery appearance. Whether this photoaging represents acceleratedchronologic aging or a separate and distinct process is not clear. Within chronically sun-exposed epidermis, there is thickening (acanthosis)and morphologic heterogeneity within the basal cell layer. Higher but irregularmelanosome content may be present in some keratinocytes, indicating prolongedresidence of the cells in the basal cell layer. These structural changes may help toexplain the leathery texture and the blotchy discoloration of sun-damaged skin. UV-A is important in the pathogenesis of photoaging in human skin, andROS are likely involved. The dermis and its connective tissue matrix are the majorsite for sun-associated chronic damage, manifest as solar elastosis, a massiveincrease in thickened irregular masses of abnormal elastic fibers. Collagen fibersare also abnormally clumped in the deeper dermis of sun-damaged skin. Thechromophore(s), the action spectra, and the specific biochemical eventsorchestrating these changes are only partially understood, although UV-A seemsto be primarily involved. Chronologically aged, sun-protected skin and photoagedskin share important molecular features including connective tissue damage andelevated matrix metalloproteinases (MMPs). MMPs are enzymes involved in thedegradation of the extracellular matrix, and UV-A induces MMP-1 and MMP-3mRNA expression, leading to enhanced collagen breakdown. In addition, UV-Areduces type I procollagen mRNA expression. Chronic Effects of Sun Exposure: Malignant One of the major known consequences of chronic skin exposure to sunlightis nonmelanoma skin cancer. The two types of nonmelanoma skin cancer are basalcell carcinoma (BCC) and squamous cell carcinoma (SCC; Chap. 83). There arethree major steps for cancer induction: initiation, promotion, and progression.Exposure of human skin to sunlight results in initiation, a step whereby structural(mutagenic) changes in DNA evoke an irreversible alteration in the target cell(keratinocyte) that begins the tumorigenic process. Exposure to a tumor initiatorsuch as UV-B is believed to be a necessary but not sufficient step in the malignantprocess, since initiated skin cells not exposed to tumor promoters do not generallydevelop tumors. The second stage in tumor development is promotion, a multistepprocess whereby chronic exposure to sunlight evokes epigenetic changes thatculminate in the clonal expansion of initiated cells and cause the development,over many years, of premalignant growths known as actinic keratoses, a minorityof which may progress to form skin cancer. Based on extensive studies it seemsclear that UV-B is a complete carcinogen, meaning that it can act as both a tumorinitiator and a promoter. The third and final step in the malignant process is malignant conversion ofbenign precursors into malignant lesions, a process thought to require additionalgenetic alterations in already transformed cells. Skin carcinogenesis is thought tobe caused by the accumulation of mutations in the tumor-suppressor gene p53 as aresult of UV-induced DNA damage. Indeed both human and murine UV-inducedskin cancers have unique p53 mutations (C →T and CC →TT transitions) that arepresent in the majority of these lesions. Studies have shown that sunscreens cansubstantially reduce the frequency of these signature mutations in p53 and candramatically inhibit the ...