Melanin Melanocyte

Neural cells convert tyrosine to epinephrine and norepinephrine (Figure 31—5). While dopa is also an intermediate in the formation of melanin, different enzymes hydroxylate tyrosine in melanocytes. Dopa decarboxylase, a pyridoxai phosphate-dependent enzyme, forms dopamine. Subsequent hydroxylation by dopamine P-oxidase then forms norepinephrine. In the adrenal medulla, phenylethanolamine-A -methyltransferase uti-hzes S-adenosyhnethionine to methylate the primary amine of norepinephrine, forming epinephrine (Figure 31-5). Tyrosine is also a precursor of triiodothyronine and thyroxine (Chapter 42). 

Melanins are prodnced in mammals in two types of cells of different developmental origin (1) the melanocytes of the skin, hair, choroids and iris and (2) the retinal pigment epithelium (RPE). Specialized organelles of the melanocytes, the melano-somes, synthesize and store eumelanins and phaeomelanins. 

Generally, the phenotype that predisposes an individual to an increased risk of skin cancer is red or blond hair, blue eyes, and fair skin. These characteristics are surrogate measure of the sensitivity of the skin to sun exposure and the tendency to develop nevi, freckles, and sunburns based on the skin type. Freckles, which may appear abruptly after the first high dose of UV radiation sun exposure, represent clones of mutated melanocytes, and their presence is associated with an increased risk of melanoma.12 The Fitzpatrick classification of skin type is used to determine the response pattern of the skin to UV radiation and assess the risk for melanoma. There are six Fitzpatrick skin types Type I skin always burns and never tans, type II skin burns easily and tans rarely, type III skin burns sometimes and tans usually, type IV skin burns rarely and always tans, type V skin always tans and is moderately pigmented (brown), and type VI skin always tans and is darkly pigmented (black). Fitzpatrick I and II skin types are commonly affected by NMSC and MM. The susceptibility to skin cancer, both NMSC and MM, is related to the melanin content of the skin and the skin s response to UV radiation. 

Melanin from natural sources falls into two general classes. The first component is pheomelanin (I), which has a yellow-to-reddish brown colour, and is found in red feathers and red hair. The other component is eumelanin (which has two principal components, II and III). Eumelanin is a dark brown-black compound, and is found in skin, hair, eyes, and some internal membranes, and in the feathers of birds and scales of fish. Melanin is particularly conspicuous in the black dermal melanocytes (pigment cells) of dark-skinned peoples and in dark hair and is conspicuous in the freckles, and moles of people with lighter skins. 

Copper is a component of many enzymes including amine oxidase, lysyl oxidase, ferroxidase, cytochrome oxidase, dopamine P-hydroxylase, superoxide dismutase and tyrosinase. This latter enzyme is present in melanocytes and is important in formation of melanin controlling the colour of skin, hair and eyes. Deficiency of tyrosinase in skin leads to albinism. Cu " ion plays an important role in collagen formation. 

In a study of intermediate duration, dermal application of 0.5% p-cresol for 6 weeks produced permanent depigmentation of the skin and hair of mice (Shelley 1974). A caustic effect on the skin was noted in one strain of mouse, but not another. Neither o- nor m-cresol produced any color change in the mice. The author suggests that only p-cresol is active because it mimics the structure of tyrosine, the amino acid present in melanin, so that tyrosinase acts on it, liberating free radicals that damage melanocytes. NOAEL and LOAEL values were not derived from this study because the applied dose was not reported. 

Hydroquinone interferes with the production of the pigment melanin by epidermal melanocytes through at least two mechanisms it competitively inhibits tyrosinase, one of the principal enzymes responsible for converting tyrosine to melanin, and it selectively damages melanocytes and melanosomes (the organelles within which melanin is stored). 

C. Hydroquinone inhibits the enzyme tyrosine kinase, which converts tyrosine to melanin. It also damages melanocytes. Becaplermin (A) is a recombinant human platelet-derived growth factor that is useful in enhancing wound healing. Etanercept (B) is a recombinant fusion protein approved for treatment of psoriatic arthritis and rheumatoid arthritis. Botulinum toxin (D) is a purified form of bofu-linum foxin fype A approved for fherapy of blepharospasm and sfrabismus. 

The anterior lobe secretes various trophic hormones, the posterior lobe is responsible for the secretion of oxytocin and antidiuretic hormone (vasopressin) and middle lobe secretes melanocyte-stimulating hormone (MSH) which may affect the synthesis of melanin. 

The mechanism of action of these compounds appears to involve inhibition of the enzyme tyrosinase, thus interfering with the biosynthesis of melanin. In addition, monobenzone may be toxic to melanocytes, resulting in permanent loss of these cells. Some percutaneous absorption of these compounds takes place, because monobenzone may cause hypopigmentation at sites distant from the area of application. Both hydroquinone and monobenzone may cause local irritation. Allergic sensitization to these compounds can occur. Prescription combinations of hydroquinone, fluocinolone... 

Also present in the epidermis are embedded macrophage-like Langerhans cells as well as pigmented melanocytes, cells with highly branched dendrites, which lie just above the basal stem cell layer. Each melanocyte contains hundreds of pigmented organelles called melanosomes. They contain not only the black or reddish melanin pigments but also the enzymes needed to form them (Chapter 25).n o... 

The dendrites of a melanocyte contact about 36 keratinocytes and are able to transfer melanosomes to these adjacent cells. The numbers and sizes of the melanosomes as well as melanin structure determine differences in skin color.131 Similar cells in amphibians, the melanophores, also contain light receptors p Their melanosomes are not transferred to other cells but may be either clustered near the center of the cell or dispersed. The location can be changed quickly by transport of the melanosomes along a network of microtubules allowing the animals to change in response to changes in light color.0)... 

Various stimuli, including ultraviolet irradiation of melanocytes, cause increased synthesis of melanin with a resultant tanning0 and added protection against sunburn. 

The principal pigment of human skin, hair, and eyes is melanin, which is synthesized in specialized cells, the melanocytes. They lie between the epidermis (outer layer) and the dermis (inner layer) as shown in Box 8-F. Melanocytes originate from embryonic nervous tissue and migrate into the skin by the third month of fetal life. They retain the highly branched morphology of neurons. Persons of different races all have the same numbers of melanocytes but the numbers and sizes of the pigmented melanosomes (Box 8-F) vary as does the content and chemical composition of the melanin.a d Melanosomes not only are found in the dendrites of the melanocytes but are transferred from them into adjacent epithelial cells.6 1... 

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