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PubMed1995

Dual role of melanins and melanin precursors as photoprotective and phototoxic agents: inhibition of ultraviolet radiation-induced lipid peroxidation.

Ultraviolet radiation (UVR) is one of the risk factors for skin cancer and the main inducer of melanin pigmentation, the major protective mechanism of mammalian skin against radiation damage. The melanin pigments, eumelanin and pheomelanin, are likely to be important in protection against UVR, but their precursors are generally considered as phototoxic. The available data suggest DNA damage as the mechanism of phototoxicity. However, the effect of melanin precursors on membrane damage through lipid peroxidation, another important and probably more relevant (from the point-of-view of the melanosomal confinement of these molecules) mechanism of phototoxicity, not known. As a model system for UVR-melanin-membrane interactions, we irradiated liposomes in the presence of eumelanin, pheomelanin and two of their major precursors, 5,6-dihydroxyindole (DHI) and 5-S-cysteinyldopa (SCD). The presence of the two melanin precursors substantially reduced the formation of lipid peroxidation products resulting from UVR exposure. The antioxidant activity of the melanin precursors was diminished under strong prooxidant conditions (presence of Fe3+). These results suggest that melanin precursors may have an important role in the protection of skin against the harmful effects of UVR including photocarcinogenesis.

Animals↗
PubMed2005

Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels.

PURPOSE: There are no available tumor markers detecting primary melanoma at an early stage. The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma. We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. EXPERIMENTAL DESIGN: Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal. We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. RESULTS: The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.

Adult↗
PubMed1993

Fibroblasts expressing mouse c locus tyrosinase produce an authentic enzyme and synthesize phaeomelanin.

Recent advances in the study of the molecular biology of mouse pigmentation have led to the discovery of a family of proteins involved in the control of melanin synthesis. It has been confirmed that the product of the mouse c (albino) locus is the key melanogenic enzyme tyrosinase, but study of its function and regulation have been hampered by the presence of closely related proteins within melanin-synthesising cells. To overcome these problems, we have established lines of mouse fibroblasts expressing the c locus mouse tyrosinase. Here we describe characterisation of the tyrosinase synthesised by these cells and demonstrate considerable similarity between the expressed tyrosinase and the native enzyme. The expressed tyrosinase is proteolytically cleaved to produce membrane-bound and soluble forms of the expected molecular mass and is rich in N-linked carbohydrate, suggesting that melanocytic differentiation is not a prerequisite for post-translational modification of the protein. The expressed enzyme has tyrosinase activity, but not catalase or dopachrome tautomerase activity, confirming that it is an authentic tyrosinase. Transfected fibroblasts expressing tyrosinase are shown to share several physiological characteristics with melanoma cell lines, including increased pigmentation and tyrosinase activity in response to increased cell density. Since tyrosinase is expressed under a heterologous promoter, these shared characteristics probably reflect translational or post-translational controls that operate in both non-melanocytic and melanocytic cell types. We demonstrate that pigmented fibroblasts contain the melanin synthesis intermediates 5-S-cysteinyldopa and 5-S-glutathionyl-dopa, and produce a phaeomelanin-like pigment, but do not contain detectable eumelanin. Expression of tyrosine is therefore sufficient for the synthesis of a form of melanin pigment in fibroblasts.

3T3 Cells↗
PubMed1990

Production, circulation, and excretion of melanin-related metabolites in B16 melanoma-bearing mice.

Urinary 5-S-cysteinyldopa (5-S-CD) has been used as a biochemical marker of melanoma metastasis. A method was developed for determining the eumelanin-related metabolites 5(6)-hydroxy-6(5)-methyoxyindole-2-carboxylic acids (5H6MI2C and 6H5MI2C) in small volumes of serum. We compared these indoles and 5-S-CD regarding the correlation of their production in melanoma, circulation in blood, and excretion in urine, with the weight of highly pigmented, B16 mouse melanoma. An excellent correlation was found between the serum concentration of 5H6MI2C + 6H5MI2C (r = 0.92) and 5-S-CD (r = 0.89) and tumor weight. However, the urinary excretion of 5H6MI2C + 6H5MI2C and 5-S-CD did not show any significant correlation. These results suggest that 5H6MI2C + 6H5MI2C and 5-S-CD in serum may better reflect melanoma progression than those in urine. Furthermore, comparison of the contents of these melanin-related metabolites between highly pigmented and less pigmented B16 melanomas suggests that 5-S-CD may be accumulated in pigmented melanoma by virtue of binding to melanin and that catechol-O-methyltransferase (COMT) may play a regulatory role in pigmentation.

Animals↗
PubMed1990

5-S-cysteinyldopac in human urine.

5-S-Cysteinyldopac, a compound hitherto demonstrated only in brain tissue, has been isolated and quantified in urine. The urines from 12 individuals were found to contain 20 +/- 9.1 micrograms 5-S-cysteinyldopac/24 hours. Incubation of 5-S-cysteinyldopamine with MAO-containing tissue did not give any formation of 5-S-cysteinyldopac, indicating that this compound is formed by nucleophilic addition of cysteine directly to dopac. The findings give further evidence for a small but significant non-specific oxidation of endogenous catechol derivatives in vivo, a fact to be considered when using 5-S-cysteinyldopa as a measure of pigment metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Co-regulation of melanin precursors and tyrosinase in human pigment cells: roles of cysteine and glutathione.

Glutathione (GSH) and cysteine (CysH) have both been implicated in the biogenesis of the pheomelanin precursor 5-S-cysteinyldopa (5-S-CD). However, recent studies have shown that only CysH is transported across the membrane of isolated melanosomes, and that the positive regulation of CysH in pigment cells leads to an increased production of 5-S-CD. In the present study, the question was examined as to whether melanin precursors and tyrosinase could be coregulated by cellular thiols. To address this issue, the levels of CysH and GSH were varied in normal melanocytes and melanoma cells using buthionine sulfoximine (BSO), an inhibitor of GSH biosynthesis. Treatment with 50-100 microM BSO decreased GSH levels to less than 10% of control, and increased CysH levels between two- and five-fold in both cell types. Concomitant with this, an increase in the ratio of 5-S-CD to DOPA and a decrease in the pigment content of the cells were observed. The decrease in cell pigmentation was associated with strong decreases in tyrosine hydroxylase activity and 14C-melanin production. Only melanoma cells showed a modified tyrosinase isozyme pattern on Western immunoblots in response to BSO, while the mRNA expression of tyrosinase and TRP-1 were unchanged in both cell types. These results suggest that the balance between CysH and GSH, which is partly determined by the rate of utilization of CysH for GSH biosynthesis, regulates not only the levels of 5-S-CD and DOPA but also the melanogenic activity of pigment cells. Since DOPA functions as a cofactor in the monophenolase reaction of tyrosinase, it is proposed that the ratio of 5-S-CD to DOPA may be an important factor in the regulation of tyrosinase activity in situ.

Buthionine Sulfoximine↗
PubMed1991

Melanocytes, moles and melanoma--a study on UV effects.

To investigate the UV effect on epidermal melanocytes, 21 volunteers and 11 patients with dysplastic nevus syndrome (DNS) received UVB irradiation three times weekly during 17 days. Skin biopsies were taken before and three weeks after the last irradiation (on day 37) from exposed and covered buttock skin. The epidermal melanocyte population density was estimated in dopa-stained split skin preparations. The biopsies taken on day 37 revealed that repeated UVB irradiation induces an increase in the number of melanocytes not only in exposed but also in covered skin. This increased mitotic activity might be a link between sun exposure and melanoma development in covered skin. The size of the proliferative response was inversely correlated to the basal melanocyte number. The larger population increase in skin with few melanocytes might amplify the propagation of DNA damage and increase the likelihood of tumor development. The pigment metabolite 5-S-cysteinyldopa (5-S-CD) was measured in urine before the irradiation and twice weekly until day 38. No correlation was found between the basal 5-S-CD excretion and the size or activity of the melanocyte organ, suggesting that the basal 5-S-CD excretion is mainly of non-melanocytic origin. Despite numerous nevi, DNS-patients did not differ from controls in their 5-S-CD excretion. The normal upper range for the tumor maker 5-S-CD is therefore valid in these melanoma-prone subjects. During the irradiation, subjects with a low tanning ability developed a more pronounced erythema and excreted more 5-S-CD than those with a good tanning ability. This suggests that the UVB-induced 5-S-CD excretion is rather due to melanocyte damage than to an increased melanin synthesis. To investigate the influence of sun exposure on the development of nevi and melanoma (CMM), the distribution over the body surface of CMM, common nevi (CN) greater than or equal to 2 mm and dysplastic nevi (DN) was registered in 121 melanoma patients and 310 controls. Four times as many nevi were found in a sun-exposed area than in a comparable sun-protected area, demonstrating that sun exposure plays an important role in nevus development. Subjects with DNA had a larger difference in nevus counts between the two areas than subjects without DN, indicating a different UV-dose and/or a higher sensitivity to the "nevogenic" effect of UV-light than subjects without DN.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1985

Urinary excretion of melanocytic metabolites in fertile women.

Pregnant women and women taking oral contraceptives show urinary excretion values of 5-S-cysteinyldopa and of 6-hydroxy-5-methoxyindole-2-carboxylic acid in the same range as nonpregnant women not taking oral contraceptives. The excretion of these melanoma markers can therefore be used in in the biochemical diagnosis of metastatic melanoma in pregnancy and in women taking oral contraceptives.

Adult↗
PubMed1986

Oxidation of dopa in the skin of black and albino mice.

The dopa oxidase activity of tyrosinase in the skin from albino and black mice was assayed using a technique based on the formation of two diastereomers of 5-S-cysteinyldopa when incubating tissue extracts with both L-dopa and D-dopa as substrates in the presence of cysteine. The amounts of 5-S-L-cysteinyl-L-dopa and 5-S-L-cysteinyl-D-dopa formed were then determined. In the extract from black mouse skin the L-L-diastereomer was produced in more than ten times the amount of the L-D-diastereomer. This stereospecific dopa-oxidation is indicative of the presence of tyrosinase and corresponds well with earlier determinations of the rates of oxidation for human tyrosinase, using L-dopa and D-dopa as substrates. Stereospecific dopa oxidation was absent in albino skin, and the nonspecific dopa-oxidation was two orders of magnitude less than the dopa oxidation in black skin. The study demonstrates the lack of tyrosinase activity in albino skin, and quantifies the non-specific dopa oxidation. The lack of tyrosinase activity in the eluates from albinotic skin was found not to be due to the presence of a tyrosinase inhibitor.

Albinism↗
PubMed1986

Trichochromuria in melanosis of melanoma.

Two patients with metastasizing melanoma and diffuse melanosis have previously been reported to excrete large quantities of trichochromes in the urine. The present study describes 2 further melanoma patients with diffuse melanosis and trichochromuria. The hair of one of the patients which had been red in childhood and turned brown in adult age returned to red with the appearance of melanosis. Normal excretion of a methylated melanocytic metabolite, 6-hydroxy-5-methoxyindole-2-carboxylic acid, was observed in this patient, possibly indicating exhaustion of the methylating system. The other patients excreted large quantities of 6-hydroxy-5-methoxyindole-2-carboxylic acid. Both patients showed highly increased excretion of 5-S-cysteinyldopa. Both patients with melanosis exhibited fine electrone-dense granules in lysosomes of dermal histiocytes. The findings support the concept that trichochromes or similar pigments in dermal histiocytes are responsible for diffuse melanosis in melanoma patients.

Adult↗
PubMed1988

Melanin-related metabolites in urine of B16 melanoma-bearing mice.

5-S-Cysteinyldopa (5-S-CD), a pheomelanin precursor, has been used as a biochemical marker of melanoma metastasis. Recently, 5-hydroxy-6-methoxyindole-2-carboxylic acid (5H6MI2C), a eumelanin-related metabolite, was shown to reflect well the degree of skin pigmentation. We measured the urinary excretion of 5H6MI2C and 5-S-CD in mice bearing B16 melanoma to determine which of the two markers better reflects the progression of melanoma. The urinary excretion of both 5H6MI2C and 5-S-CD increased rapidly in parallel with the tumour volume. The highest values for the two metabolites in melanoma-bearing mice were three orders of magnitude higher than those in control mice. However, 5H6MI2C had a higher excretion level at the early stage of melanoma progression, while 5-S-CD had a higher excretion level at the later stage.

Animals↗
PubMed1989

Correlation between urinary melanin-related metabolites and tumour weight in melanoma-bearing mice.

Melanoma tissues produce not only 5-S-cysteinyldopa (5-S-CD), a pheomelanin precursor, but also 5,6-dihydroxyindoles, eumelanin precursors. We compared 5-S-CD and eumelanin-related metabolites regarding the correlation of their production in melanoma and excretion in urine, versus the weight of B16 mouse melanoma. It was found that B16 melanoma tissues produce 5,6-dihydroxyindole-2-carboxylic acid and its two O-methyl derivatives, the latter of which are partly conjugated with sulphuric acid and then excreted. These indolic metabolites are referred to as total indoles. Both total indoles and 5-S-CD in melanoma and in urine correlated well with each other and reflected the tumour weight. Total indoles had a four-fold greater level of excretion than 5-S-CD, suggesting that the urinary excretion of total indoles is a quantitatively more significant marker of melanoma progression in this melanoma.

Animals↗
PubMed1986

Metabolism of 5-S-glutathionyldopa.

5-S-Glutathionyldopa is oxidized at incubation with tyrosinase and dopa producing a black pigment. The reaction proceeds with the formation of two chromophores with absorption spectra similar to those of dopachrome and melanochrome, respectively. Zn2+ catalyses the formation of the melanochrome-like compound. The oxidation of 5-S-glutathionyldopa by dopaquinone, formed by the action of human tyrosinase and mushroom tyrosinase, is considerably slower than that of 5-S-cysteinyldopa. The higher oxidation potential of 5-S-glutathionyldopa, and/or the greater number of dopaquinone molecules necessary for pigment formation from 5-S-glutathionyldopa and/or the formation of tyrosinase-inhibiting products from 5-S-glutathionyldopa can explain the slower oxidation of this compound. The oxidative pathways suggested for 5-S-glutathionyldopa by the present findings may be relevant both in the melanocyte and in non-specific oxidation of cathechols occurring in other cells.

Basidiomycota↗
PubMed1988

Biochemical observations in UV-induced pigmentation.

The biochemical events in the melanocytes resulting from stimulation of pigmentation by exposure to ultraviolet (UV) irradiation are correlated to changes in specific metabolites in the plasma and in the urine. A compound produced in the melanocyte by nucleophilic addition of cysteine to dopaquinone, 5-S-cysteinyldopa, is present in increased quantities in the plasma and in the urine after different types of pigment-producing UV exposure. Similarly, a methylated indolic metabolite, 6-hydroxy-5-methoxyindole-2-carboxylic acid, appears in increased amounts in the urine after UV exposure of the skin. UVA does not produce inflammation or pigmentation in skin that is anoxic at the time of irradiation. In contrast, inflammation and pigment response to UVB and PUVA are not dependent on oxygenation of the skin at the time of exposure.

Cysteinyldopa↗
PubMed1982

5-OH-dopa, product of and substrate for tyrosinase.

The formation of 5-OH-dopa on incubation of tyrosine or dopa with mushroom tyrosinase was studied. Dopa oxidase activity was defined by measuring the formation of 5-S- and 2-S-cysteinyldopa from dopa in the presence of excess amounts of cysteine. This procedure quantitating the immediate nucleophilic reaction products of dopaquinone constitutes a new method for assessing tyrosinase activity. The rate of 5-OH-dopa formation from dopa was similar to that of the formation of dopa from tyrosine. The rate of dopaquinone formation was one order of magnitude higher. When tyrosine was oxidized in the presence of ascorbic acid, 5-OH-dopa formation represented 14% of the original amount of tyrosine. At low concentration of dopa, formation of 5-OH-dopa was proportional to the dopa concentration. At high concentrations the relative quantity of 5-OH-dopa formed decreased. Tyrosine in high concentrations inhibited the formation of 5-OH-dopa from dopa. 5-OH-dopa proved to be a substrate for tyrosinase. The rate of oxidation of 5-OH-dopa was similar to that of dopa. The oxidation products of 5-OH-dopa were transformed into relatively stable fluorophores.

Basidiomycota↗
PubMed1983

Liquid-chromatographic determination of 5-S-L-cysteinyl-L-dopa with electrochemical detection in urine prepurified with a phenylboronate affinity gel.

A phenylboronate affinity gel has been investigated for use in the prepurification of urine before "high-performance" liquid chromatography and electrochemical determination of 5-S-L-cysteinyl-L-dopa. At pH 5.6 this naturally occurring 5-S-cysteinyldopa was adsorbed on a phenylboronate column and was quantitatively eluted with trichloroacetate, pH 3.0. This pretreatment of urine before "high-performance" liquid chromatography produced satisfactory chromatographic separations, and the results were further improved when the purification procedure also included treatment on a cation exchanger. By using 5-S-D-cysteinyl-L-dopa--a diastereomer to 5-S-L-cysteinyl-L-dopa--as an internal standard, we have developed a practical routine method for the quantitative determination of urinary 5-S-L-cysteinyl-L-dopa. The precision (CV = 2.4%) and analytical recovery (96.9%, SD 5.3%) were satisfactory and the results obtained correlated well with a previously described method.

Boronic Acids↗
PubMed1980

Tumorigenicity of human malignant melanocytes in nude mice in relation to their differentiation in vitro.

Of 16 cell lines derived from 12 human melanomas obtained from 11 patients, all were established as permanent cell lines: 7 from primary tumors and 9 from metastatic tumors. Study of the early subcultures and established cell lines showed that melanocytes passed through a phase of dedifferentiation during which they took on a fibroblast-like appearance and were hypodiploid and nontumorigenic in nude (thymus-deficient) mice. Phenotypic modulation in vitro was shown to be dependent on the culture medium. The lines varied considerably in karyologic and phenotypic expression (as assessed by morphologic appearance and 5-S-cysteinyldopa production). Fibroblast-like, epithelioid, nonpigmented, achromic, and pigmented cells were obtained from the same tumor. Heterotransplantation into nude mice revealed wide variations in tumorigenicity: The latency of the tumors, their size, and infrequent metastases bore no relationship to the phenotypic modulation of the melanocytes as expressed in vitro. Melanogenesis is therefore not related to malignancy; they are two independent characteristics.

Animals↗
PubMed1977

Glutathionedopa in malignant melanoma.

A human melanoma metastasis was found to contain a substance identical with synthetic glutathionedopa when examined by means of an automatic amino acid analyser, chromatography on a Dowex-50 column, thin-layer electrophoresis, and by fluorimetry. The presence of glutathionedopa in melanoma tissue and of enzymes capable of hydrolysing the glutathione moiety of the molecule, together with the absence of glutathionedopa in the urine, suggest that glutathionedopa is an intermediate substance in the formation of 5-S-cysteinyldopa.

Cysteinyldopa↗