Chapter 057. Photosensitivity and Other Reactions to Light (Part 2)

Molecular Targets for UVR-Induced Skin Effects Epidermal DNA, predominantly in keratinocytes and in Langerhans cells (LCs), which are dendritic antigen-presenting cells, absorbs UV-B and undergoes structural changes including the formation of cyclobutane dimers and 6,4photoproducts. These structural changes are potentially mutagenic and can be repaired by mechanisms that result in their recognition and excision and the reestablishment of normal base sequences. The efficient repair of these structural aberrations is crucial, since individuals with defective DNA repair are at high risk for the development of cutaneous cancer. ...
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Chapter 057. Photosensitivity and Other Reactions to Light (Part 2) Chapter 057. Photosensitivity and Other Reactions to Light (Part 2) Molecular Targets for UVR-Induced Skin Effects Epidermal DNA, predominantly in keratinocytes and in Langerhans cells(LCs), which are dendritic antigen-presenting cells, absorbs UV-B and undergoesstructural changes including the formation of cyclobutane dimers and 6,4-photoproducts. These structural changes are potentially mutagenic and can berepaired by mechanisms that result in their recognition and excision and thereestablishment of normal base sequences. The efficient repair of these structuralaberrations is crucial, since individuals with defective DNA repair are at high riskfor the development of cutaneous cancer. For example, patients with xerodermapigmentosum (XP), an autosomal recessive disorder, are characterized by variablydeficient repair of UV-induced photoproducts, and their skin phenotype oftenmanifests the dry, leathery appearance of prematurely photoaged skin as well asbasal cell and squamous cell carcinomas and melanoma in the first two decades oflife. Studies in mice using knockout gene technology have verified the importanceof functional genes regulating these repair pathways in preventing thedevelopment of UV-induced cancer. Furthermore, incorporation of a bacterialDNA repair enzyme, T4N5 endonuclease, into liposomes in a product applied toskin of patients with XP selectively removes cyclobutane pyrimidine dimers andreduces the degree of solar damage and skin cancer. DNA damage in LCs maycontribute to the known immunosuppressive effects of UV-B (see ImmunologicEffects, below). Cutaneous Optics and Chromophores Chromophores are endogenous or exogenous chemical components that canabsorb physical energy. Endogenous chromophores are of two types: (1)chemicals that are normal components of skin, including nucleic acids, proteins,lipids, and 7-dehydrocholesterol, the precursor of vitamin D; and (2) chemicals,such as porphyrins, synthesized elsewhere in the body that circulate in thebloodstream and diffuse into the skin. Normally, only trace amounts of porphyrinsare present in the skin, but in selected diseases known as the porphyrias (Chap.352), increased amounts are released into the circulation from the bone marrowand the liver and are transported to the skin, where they absorb incident energyboth in the Soret band, around 400 nm (short visible), and to a lesser extent in thered portion of the visible spectrum (580–660 nm). This results in the generation ofreactive oxygen species that can mediate structural damage to the skin, manifest aserythema, edema, urticaria, or blister formation. Acute Effects of Sun Exposure The acute effects of skin exposure to sunlight include sunburn and vitaminD synthesis. Molecular targets for UVR in addition to DNA include molecularoxygen leading to the generation of reactive oxygen species (ROS), cellmembranes, and urocanic acid. Sunburn This painful skin condition is caused predominantly by UV-B. Generallyspeaking, an individuals ability to tolerate sunlight is inversely proportional to thedegree of melanin pigmentation. Melanin, a complex tyrosine polymer, issynthesized in specialized epidermal dendritic cells known as melanocytes and ispackaged into melanosomes that are transferred via dendritic process intokeratinocytes, thereby providing photoprotection and simultaneously darkeningthe skin. Sun-induced melanogenesis is a consequence of increased tyrosinaseactivity in melanocytes that in turn is a consequence of a human gene, themelanocortin1 receptor (MCIR), that accounts for the wide variation in human skinand hair color. Human MCIR encodes a 317-amino-acid G-coupled receptor(melanocortin receptor) that binds α-melanocyte-stimulating hormone. This leadsto increased intracellular cyclic AMP and protein kinase A, followed by increasedtranscription of microphthalmia transcription factor (MITF) that regulatesmelanogenesis. MCIR mutations account for population differences in skin color,ability to tan, and cancer susceptibility. The Fitzpatrick classification of humanskin is a function of the efficiency of the epidermal-melanin unit and can usuallybe ascertained by asking an individual two questions: (1) Do you burn after sunexposure? and (2) Do you tan after sun exposure? The answers to these questionspermit division of the population into six skin types varying from type I (alwaysburn, never tan) to type VI (never burn, always tan) (Table 57-1). Table 57-1 Skin Type and Sunburn Sensitivity (FitzpatrickClassification) Type Description I Always burn, never tan II ...