Melanocytes, tyrosinase

Parahydroxyphenylpyruvic, phenylacetic, and phenyllactic acids inhibit tyrosinase, but whereas the first of these compounds is a potent inhibitor, the others are only weak inhibitors. It seems that if this inhibitory effect were important in phenylketonuria, pigment metabolism would be more apparently altered in tyrosinosis than in phenylketonuria, which seems not to be the case. However, the enzyme block might explain why small doses or dietary amounts of tyrosine have no effect on the pigmentation of patients with phenylketonuria. Only when large doses of the amino acid are administered are pigmentation and epinephrine biosynthesis restored to normal, probably because tyrosine competes with phenylalanine metabolites for melanocyte tyrosinase and dopa decarboxylase. 

Dooley, T.P. (1999) Inhibitors of Mammalian Melanocyte Tyrosinase In Vitro Comparisons of Alkyl Esters of Gentisic Acid with Other Putative Inhibitors. Biochem. Pharmacol, Vol.57, p>p.663-672. 

Furthermore, a melanocyte line that has reverted in culture from albino to wild type has restored the cysteine codon at position 85 (Jackson and Bennett, 1990). In vivo studies (see below) proved that the c-locus encodes tyrosinase and showed that expression of a tyrosinase minigene rescues the albino phenotype (Yokoyama et al., 1990 Tanaka et al., 1990 Beermann et al., 1990). 

Figure 5. Tyrosinase gene expression in melanocytes of the hair follicle. Bright field photographs show sections of skin of 4-day-old albino mice. Bar represents 50 pm.

This brief summary shows that our understanding of the basis of melanocyte-specific expression of the tyrosinase gene and the tyrosinase-related genes TRP-1 and TRP-2 is still limited. Novel approaches such as the introduction of the 70-kb-long mouse tyrosinase gene with extensive 5 flanking sequences as recently achieved (Schedl et al., 1993) allow an experimental attack of this important question. 

Bennett, D. C., Huszar, D., Laipis, P. J Jaenisch, R., and Jackson, I. J. (1990). Phenotypic rescue of mutant brown melanocytes by a retrovirus carrying a wild-type tyrosinase-related protein gene. Development 110 471-475. 

Kltippel, M Beermann.F., Ruppert, S., Schmid, E Hummler, E., and Schiitz, G. (1991). The mouse tyrosinase promoter is sufficient for expression in melanocytes and in the pigmented epithelium of the retina. Proc. Natl. Acad. Sci. USA 88 3777-3781. 

Porter, S. )., and Meyer, C. J. (1994). A distal tyrosinase upstream element stimulates gene expression in neural-crest-derived melanocytes of transgenic mice position-independent and mosaic expression. Development 120 2103-2111. 

Porter, S., Larue, L., and Mintz, B. (1991). Mosaicism of tyrosinase-locus transcription and chromatin structure in dark vs. light melanocyte clones of homozygous chinchilla-mottled mice. Dev. Genet. 12 393-402. 

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). 

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... 

Albinism The most common type, oculocutaneous albinism, results in white hair, pink skin, and an extreme photophobia owing to lack of pigment in the eye Tyrosinase of the melanocyte is absent... 

The mechanism of iris pigmentation due to latanoprost is unknown. In an in vitro experiment using uveal melanocytes, the addition of latanoprost increased melanin content, melanin production, and tyrosinase activity (18). Alpha-methyl-para-tyrosine, an inhibitor of tyrosinase (the enzyme that transforms tyrosine to levodopa), completely prevented the latanoprost-induced stimulation of melanogenesis. 

Tissue-specific Tyrosinase, tyrosinase related protein-1 Melanocytes [123-128]... 

Melanin granules are secreted by melanocytes in the hair papilla and distributed to keratin in the hair cortex and inner layers of the hair sheath during normal development. Melanogenesis is subject to hormonal control and has been the focus of intensive genetic studies. Two main forms of melanin exist in human skin—eumelanin and phaeomelanin, both of which are derived from tyrosine through the action of tyrosinase (a cupro-enzyme) and possibly other key enzymes (with nickel, chromium, iron, and manganese as cofactors). Tyrosine is converted to dihydroxyphenylalanine and, via a series of intermediate steps, to indole-5,6-quinone, which polymerizes to eumelanin. Phaeomelanins are produced by a similar mechanism but with the incorporation of sulfur (as cysteine) by a nonenzymatic step in the oxidation process. 

Tyrosine, itself a degradation product of phenylalanine (Sec. 15.1), is initially converted to 3.4-dihydroxyphenylalanine (dopa), and the corresponding do pa quinone, by the copper-containing enzyme tyrosinase. Tyrosinase is found in melanocytes and is a mixed-function oxidase. It catalyzes the following reaction ... 

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