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PubMed1999

A New Insight in the Biosynthesis of Pheomelanins: Characterization of a Labile 1,4-Benzothiazine Intermediate.

It has long been known that pheomelanins, the distinctive pigments of red hair and celtic skin, arise by the oxidative cyclization of cysteinyldopas, mainly the 5-S-isomer 1, via 1,4-benzothiazines. However, the nature and reactivity of these intermediates have remained poorly defined. In an reexamination of the oxidation of 1, in aqueous buffers at physiological pHs, a hitherto unknown labile intermediate was identified and formulated as the 3-hydroxy-3,4-dihydro-1,4-benzothiazine 5 based on direct NMR analysis of the reaction mixture and conversion to the stable benzothiazines 3 and 4 under different conditions. Structure 5 was further supported by oxidation of the model compound 6 leading to the analogous more stable 2,2-dimethyldihydro-1,4-benzothiazine 9.

Journal Article↗
PubMed2000

Chemical analysis of melanins and its application to the study of the regulation of melanogenesis.

Melanins are difficult to characterize because of their intractable chemical properties, the heterogeneity in their structural features, and the lack of methods to split melanin polymers into monomer units. To overcome this difficulty, we developed a rapid and sensitive method for quantitatively analyzing eumelanin and pheomelanin in biological samples that is based on the formation of pyrrole-2,3,5-tricarboxylic acid and/or aminohydroxyphenylalanine followed by HPLC determination. The method has been applied to the study of melanogenesis. The results summarized in this review are: 1) Biochemical studies show that in the process of mixed melanogenesis, cysteinyldopas are produced first, which are then oxidized to give pheomelanin; following cysteine depletion, eumelanin is then deposited on the preformed pheomelanin. 2) In vitro and in vivo studies show that tyrosinase activity is the most important factor that regulates the switch of melanogenesis, with lower tyrosinase activities favoring pheomelanogenesis; further suppression of melanogenesis results in a lack of pigment production. 3) In cultured melanocytes, the concentrations of tyrosine and cysteine, and their ratio in the medium, are important in determining the concentrations of eumelanin and pheomelanin produced and their ratio in the cells. In conclusion, our HPLC microanalytical method for characterizing eumelanin and pheomelanin has become a useful tool for the study of melanogenesis.

Animals↗
PubMed2000

Intracellular vesicular trafficking of tyrosinase gene family protein in eu- and pheomelanosome biogenesis.

The intracellular vesicular trafficking in the melanosome biogenesis (melanogenesis) is reviewed with the incorporation of our own experimental findings. The melanosome biogenesis involves four stages of melanosome maturation, which reflect the transport of structural and enzymatic proteins from Golgi (trans-Golgi network: TGN) to the melanosomal compartment and their organization therein. The major melanosomal proteins include tyrosinase gene family protein (tyrosinase and tyrosinase-related protein; TRP), lysosome-associated membrane protein (Lamp) and gp100 (pmel 17). They are glycosylated in the endoplasmic reticulum, and transported by vesicles from the TGN to the melanosomal compartment. During the formation of transport vesicles, they assemble on the cytoplasmic face of the TGN to select cargo by interacting directly or indirectly with coat proteins. Tyrosinase and TRP-1 possess the dileucine motifs at the cytoplasmic domain, to which adapter protein-3 binds to transport them from the TGN to stage I melanosomes (related to late endosomes) and then to stage II melanosomes. A number of small guanosine triphosphate-binding proteins, including rab 7, appear to be involved in this vesicular transport. Phosphatidyl inositol 3 kinase also regulates this membrane trafficking of melanosomal glycoprotein. Eumelanogenesis is controlled by melanocyte-stimulating hormone, and all three tyrosinase gene family proteins are transported from the TGN to stage II melanosomes that are elliposoidal and contain the structural matrix of filaments/lamellae. In contrast, pheomelanogenesis is primarily regulated by agouti signal protein, and only tyrosinase is transported from stage I melanosomes to stage II melanosomes that are spherical and related to lysosomes. Because of the absence of TRP-1 and TRP-2 in pheomelanogenesis, it may be suggested that tyrosinase is involved in lysosomal degradation after forming dopaquinone, to which the cysteine present in the lysosomal granule binds to form cysteinyldopas that will then be auto-oxidized to become pheomelanin.

Animals↗
PubMed2000

Serological markers for melanoma.

We present a review of current literature concerning the significance of serological markers in melanoma patients. Results for cytokines, cytokine receptors, cell adhesion molecules, S100 protein, melanoma inhibitory activity, tissue-specific reverse transcription-polymerase chain reaction, neurone-specific enolase, lipid-bound sialic acid and melanin metabolites such as 5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid are discussed. For most of these substances, serum levels are more pronounced in the more advanced stages of disease. Therefore, these markers seem to have no place in the early detection of melanoma. On the other hand, sensitivity in the advanced stages of disease seems to be < 100%, compromising their use as a new staging procedure. Some markers show promising results as a possible prognostic factor in the early detection of disease progression or in the prediction of therapy outcome. If confirmed by further studies, this could direct future therapeutic strategies and could help to select patients who would benefit most from more aggressive (adjuvant) therapies. In addition, the study of some of these substances could add to the knowledge of tumour biology and immunology.

Biomarkers, Tumor↗
PubMed2006

Linking adhesive and structural proteins in the attachment plaque of Mytilus californianus.

The byssal attachment of California mussels Mytilus californianus provides secure adhesion in the presence of moisture, a feat that still eludes most synthetic polymers. Matrix-assisted laser desorption ionization mass spectrometry was used to probe the footprints of byssal attachment plaques on glass cover slips for adhesive proteins. Besides the abundant mcfp-3 protein family (Zhao, H., Robertson, N. B., Jewhurst, S. A., and Waite, J. H. (2006) J. Biol. Chem. 281, 11090-11096), two new proteins, mcfp-5 and mcfp-6, with masses of 8.9 kDa and 11.6 kDa, respectively, were identified in footprints, partially characterized and completely sequenced from a cDNA library. mcfp-5 resembles mcfp-3 in its basic pI and abundant 3,4-dihydroxyphenyl-L-alanine (Dopa; 30 mol %), but is distinct in two respects: it is more homogeneous in primary sequence and is polyphosphorylated. mcfp-6 is basic and contains a small amount of Dopa (<5 mol %). In contrast to mcfp-3 and -5, tyrosine prevails at 20 mol %, and cysteine is present at 11 mol %, one-third of which remains thiolate. Given the oxidative instability of Dopa and cysteine at pH 8.2 (seawater), we tested the hypothesis that thiols serve to scavenge dopaquinones by adduct formation. Plaque footprints were hydrolyzed and screened for cysteine dopaquinone adducts using phenylboronate affinity chromatography. 5-S-Cysteinyldopa was detected at nearly 1 mol %. The results suggest that mcfp-6 may provide a cohesive link between the surface-coupling Dopa-rich proteins and the bulk of the plaque proteins.

Adhesiveness↗
PubMed1996

Agouti alleles alter cysteine and glutathione concentrations in hair follicles and serum of mice (A y/a, A wJ/A wJ, and a/a).

Ectopic overexpression of the agouti protein in the lethal yellow (A y/a) mouse causes a yellow coat as well as the lethal yellow syndrome. Presence of thiols like glutathione (GSH) or cysteine (Cys) may regulate the conversion of dopaquinone to phaeomelanin in hair follicle melanocytes. GSH also plays important roles in cellular health and maintenance. Cys and GSH were measured using high-performance liquid chromatography in hair follicles and serum of A wJ/A wJ (agouti), A y/a (yellow), and a/a (black) mice over a 20-d hair growth regeneration period. Agouti alleles modulate thiol concentrations. A y/a hair follicles exhibited higher total thiol levels and an increased ratio of Cys to GSH. A wJ/A wJ mice showed intermediate levels, while a/a mice had lowest total thiol concentrations and a decreased ratio of Cys to GSH. Hair follicle cysteine concentrations showed yellow > agouti > black (p < 0.01). In all genotypes, unplucked skin and day 0 hair follicles showed GSH as the major thiol, but a shift to predominantly Cys on peak melanogenic days was seen. Presence of high concentrations of free cysteine support the hypothesis of phaeomelanin synthesis via cysteinyldopas. The A y/a mouse had the most dramatic follicular thiol changes as well as a depression in serum thiols. An altered thiol metabolism in these and other A y/a tissues might impair normal cell functioning to contribute to the lethal yellow syndrome.

Agouti Signaling Protein↗
PubMed1994

High plasma level of a eumelanin precursor, 6-hydroxy-5-methoxyindole-2-carboxylic acid as a prognostic marker for malignant melanoma.

Melanin synthesis is a biologic property unique to the melanocyte. It is highly elevated in malignant melanoma with the production of both eumelanin (brown/black pigment) and pheomelanin (yellow/red pigment), dihydroxyindole (DHI) and cysteinyldopa (CD), respectively, being major precursors. Melanin metabolites are often released in the urine of patients with disseminated melanoma metastasis (melanuria). To establish a better method for the detection of occult melanoma this study compares the plasma levels of a pheomelanin metabolite, 5-S-CD, and a eumelanin metabolite, 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C), in melanoma and non-melanoma patients and correlates them with tumor thickness and melanoma metastasis. We found a) that the normal plasma levels of 5-S-CD and 6H5M12C are less than 2.22 ng/ml and 1.04 ng/ml, respectively; b) that the group with the normal 6H5MI2C plasma level does not have any metastasis, whereas a normal 5-S-CD level is seen in both non-melanoma and melanoma patients with and without metastasis; c) that a high plasma 6H5MI2C level is seen in all melanoma patients with tumor thickness more than 3.0 mm regardless of the presence or absence of metastasis, whereas in thinner melanoma patients this is seen only in positive metastasis group; and d) that all melanoma patients with positive metastases showed a high plasma 6H5MI2C level (more than 1.75 ng/ml). We conclude that the measurement of plasma levels of melanin metabolites provides a method for detecting occult melanoma metastasis and estimating the prognosis of melanoma patients, plasma 6H5MI2C level being more sensitive and reliable than that of 5-S-CD, and its increased level being a high risk factor.

Biomarkers, Tumor↗
PubMed1983

Quantitative analysis of eumelanin and pheomelanin in hair and melanomas.

In this study, a method is provided for analyzing quantitatively the content and the class of melanin pigments in the tissues, e.g., hair and melanoma. The method is simple and rapid because it does not require the isolation of melanins from the tissues. The rationale was that permanganate oxidation of eumelanin yields pyrrole-2,3,5-tricarboxylic acid (PTCA) as its major pyrrolic product, which may serve as a quantitatively significant indicator of eumelanin, while hydriodic acid hydrolysis of pheomelanin yields amino-hydroxyphenylalanine (AHP) as a specific indicator of pheomelanin. The degradation products, PTCA and AHP, were determined by high-performance liquid chromatography. Sepia melanosome-melanin and synthetic 5-S-cysteinyldopa-melanin served as reference standards of eumelanin and pheomelanin, respectively. Our method provided data that corresponded well to the content and class of melanins in normal hair. Based on this control study, it was found that the melanins in the melanosomes of both B16 and Harding-Passey (HP) melanomas were eumelanic and that the melanin content in B16 melanosomes was more than 10 times higher than that in HP melanosomes, though these two melanosomes revealed distinct colors and ultrastructures, i.e., brown-black, eumelanosome-like granules in B16 and reddish- or light-brown, pheomelanosome-like granules in HP.

Animals↗
PubMed1987

Melanin-related metabolites as markers of the skin pigmentary system.

Three different groups of chemical intermediates are known to be formed during the synthesis of melanin in melanocytes: phenolic compounds, phenolic thio-conjugates, and indolic compounds. All these substances and their metabolites can be detected in urine. We measured the urinary excretion of 3,4-dihydroxyphenylalanine (dopa), 5-S-cysteinyldopa (5-S-CD), and 2 indolic compounds, namely 5-hydroxy-6-methoxyindole (5H6MI) and 5-hydroxy-6-methoxyindole-2-carboxylic acid (5H6MI2C) in urine samples of 4 groups of people with different contents of cutaneous melanin: Asian group, white group, and 2 groups of whites 1 with vitiligo and 1 with tyrosinase-negative oculocutaneous albinism. Dopa and 5-S-CD were determined with the method using high-performance liquid chromatography with an electrochemical detection. Indolic substances were measured by mass fragmentography with deuterium-labeled internal standards. Comparison of the melanin-related metabolites excreted in urine of people with different capacities for melanin biosynthesis indicates that, of all measured substances, 5H6MI2C is the best urinary marker of melanin formation in the skin pigmentary system.

Adolescent↗
PubMed1992

Alteration of melanoma melanogenesis by phenotypic modifiers.

Human melanoma cells (MM96E) were incubated with a phenotypic modifier (L-ethionine) to compare its effects on phenotypic expression with those induced by sodium butyrate and dimethyl sulfoxide. In contrast to the latter agents, L-ethionine (8mM) failed to arrest the cell cycle at the G1 phase or to inhibit colony formation ability after 48 hr incubation. Tyrosinase activity changed in parallel with 5-S-cysteinyldopa (5-S-CD) content during treatment with sodium butyrate or dimethyl sulfoxide. Tyrosinase was inhibited in L-ethionine-treated cells, probably because of metabolism of L-ethionine to sulfhydryl compounds; this remains to be clarified. Gamma-glutamyl transpeptidase activity changed inversely with tyrosinase activity after sodium butyrate or dimethyl sulfoxide incubation, whereas L-ethionine did not significantly alter the enzyme activity. In addition, only sodium butyrate induced alkaline phosphatase activity. L-ethionine was less effective than sodium butyrate or dimethyl sulfoxide in inhibiting expression of the B8G3 melanosomal antigen, as determined by Western blotting. These results suggest that phenotypic modifiers (differentiation inducers) affect melanoma cells in various ways and that melanogenesis therefore reflects only one aspect of differentiation in pigment cells.

Alkaline Phosphatase↗
PubMed2005

A case of epidermotropic metastatic malignant melanoma with multiple nodular lesions of the scalp.

Epidermotropic metastatic malignant melanoma (EMMM) is a form of metastatic malignant melanoma that has dermal cell nests with epidermotropism and specific histopathological features. We report a patient with eight nodular lesions of the scalp with histopathological findings compatible with EMMM. The tumors developed one year before consultation and increased in size simultaneously. The histopathological findings of all eight tumors were very similar. The tumor cells were located mainly in the dermis and partly in the basal layer of the epidermis. They contained melanin pigments and were positive for anti-HMB45 antibody. The tumors did not respond to combination chemotherapy with dacarbazine, nimustine, vincristine, and interferon-beta. Therefore, all the tumors were surgically removed. No local relapse, distant metastasis or re-elevation of plasma 5-S-cysteinyldopa was identified during nine months of follow-up. Histopathologically, all eight tumors lacked apparent vascular invasion, which may be related to a slow clinical course of the present case.

Aged↗
PubMedDate not supplied

Optimization of conditions for preparing synthetic pheomelanin.

Synthetic melanins are often used as the standards for natural melanins. Conditions for preparing synthetic pheomelanin from L-dopa and L-cysteine were studied under different temperatures (25 and 37 degrees C), different amounts of cysteine (1.5 and 2.0 eq), and different amounts of tyrosinase (10 and 20 mg). Effects of addition of catalase and of replacement of oxygen with air were also examined. The best preparation of pheomelanin was obtained in a good yield, when 1 mmol of L-dopa was oxidized at 25 degrees C under oxygen current in 100 ml of a pH 6.8 buffer by 20 mg of mushroom tyrosinase inn the presence of 1.5 mmol of L-cysteine. The pheomelanin thus obtained had an elemental composition and an absorption spectra that were very similar to those from a pheomelanin prepared by tyrosinase oxidation of 5-S-cysteinyldopa. Hydrolysis of synthetic pheomelanins and pheomelanic tissues with hydriodic acid gave aminohydroxyphenylalanines (AHP) as a major product and hydroxybenzothiazolylalanines as a minor product. It is proposed that AHP can be used as a specific indicator of purity of pheomelanins.

Chemical Phenomena↗
PubMed2006

Determination of eumelanin in human urine.

Normal and malignant melanocytes produce melanins and melanin-related metabolites, most of which are retained in the cells but some are secreted into the blood and then excreted in the urine. In this study, we developed a method to measure levels of eumelanin in urine samples and evaluated its clinical significance in comparison with the melanin-related metabolites 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) and 5-S-cysteinyldopa (5-S-CD), and with pheomelanin, measured after degradation as 4-amino-3-hydroxyphenylalanine (4-AHP). The method is based on the production of pyrrole-2,3,5-tricarboxylic acid (PTCA) on permanganate oxidation of eumelanin, followed by quantification by liquid chromatography. For 118 urine samples from 10 control subjects, mean urinary excretions of PTCA, 6H5MI2C, 5-S-CD and 4-AHP were 19, 67, 37 and 59 micromol/mol creatinine respectively. In melanoma patients (n = 45), the mean urinary excretions of PTCA, 6H5MI2C, 5-S-CD, and 4-AHP were 91, 926, 4070 and 3530 micromol/mol creatinine respectively. Median level of PTCA in melanoma patients was elevated 2.1-fold compared with control subjects. The degrees of elevation for 6H5MI2C, 5-S-CD, and 4-AHP were 1.8-, 22- and 6.2-fold respectively. Thus, although urinary PTCA is of little clinical value in following the progression of melanoma, urinary 4-AHP appears to be of considerable value in this respect.

Adult↗
PubMed2006

Dopaquinone redox exchange with dihydroxyindole and dihydroxyindole carboxylic acid.

A pulse radiolytic investigation has been conducted to establish whether a redox reaction takes place between dopaquinone and 5,6-dihydroxyindole (DHI) and its 2-carboxylic acid (DHICA) and to measure the rate constants of the interactions. To obviate possible confounding reactions, such as nucleophilic addition, the method employed to generate dopaquinone used the dibromide radical anion acting on dopa to form the semiquinone which rapidly disproportionates to dopaquinone. In the presence of DHI the corresponding indole-5,6-quinone (and/or tautomers) was also formed directly but, by judicious selection of suitable relative concentrations of initial reactants, we were able to detect the formation of additional indolequinone from the redox exchange reaction of DHI with dopaquinone which exhibited a linear dependency on the concentration of DHI. Computer simulation of the experimental time profiles of the absorption changes showed that, under the conditions chosen, redox exchange does proceed but not quite to completion, a forward rate constant of 1.4 x 10(6)/M/s being obtained. This is in the same range as the rate constants previously established for reactions of dopaquinone with cyclodopa and cysteinyldopa. In similar experiments carried out with DHICA, the reaction more obviously does not go to completion and is much slower, k (forward) =1.6 x 10(5)/M/s. We conclude that, in the eumelanogenic pathway, DHI oxidation may take place by redox exchange with dopaquinone, although such a reaction is likely to be less efficient for DHICA.

Computer Simulation↗
PubMed1998

Generalized melanosis in metastatic malignant melanoma: the possible role of DOPAquinone metabolites.

Generalized melanosis occurs very rarely as a complication of malignant melanoma, and the pathogenesis of this condition is still unclear. Histological examination of pigmented skin and measurements of the DOPAquinone metabolites 5-S-cysteinyldopa (5-S-CD) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) in the patient's serum and urine were carried out. Histological examination revealed basal hyperpigmentation, discrete melanoma cells and melanophages around the blood vessels and an unusual melanin deposition within collagen bundles in the dermis. The levels of 5-S-CD and 6H5MI2C were dramatically increased both in the patient's serum and urine. The deposition of DOPAquinone metabolites secreted by the melanoma cells may contribute to the unusual melanin deposition within collagen bundles in the affected dermis.

Aged↗
PubMed2005

Usefulness of the novel oncofetal antigen glypican-3 for diagnosis of hepatocellular carcinoma and melanoma.

Glypican-3 (GPC3) mRNA and protein are expressed in >80% of human hepatocellular carcinomas (HCC) but not in normal tissues except for placenta and fetal liver. The oncofetal antigen GPC3 is a glycosylphosphatidyl inositol-anchored membrane protein and may be secreted. It is a novel tumor marker for human HCC: GPC3 protein was present in sera from 40-50% of HCC patients, but was not detected in sera from patients with liver cirrhosis or chronic hepatitis, or in sera from healthy individuals. alpha-Fetoprotein (AFP) and PIVKA-II (protein induced by vitamin K absence or antagonist-II), are well known major tumor markers for HCC. Generally, AFP shows high positivity for HCC but also high false-positivity in detection assays. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) is a recently described marker of HCC. Detection of AFP-L3 shows a much higher specificity than AFP, but a lower sensitivity. On the other hand, detection of PIVKA-II shows a lower false-positivity, but is not always sensitive enough to detect low levels secreted by small HCCs. There was no correlation between the three tumor markers, AFP, PIVKA-II, and GPC3 in terms of their presence in HCC cells. All three tumor markers showed similar positivity in patients with HCC, detecting 80% of patients with the disease. GPC3 is also a novel tumor marker for the diagnosis of human melanoma, especially in the early stages of the disease. Expression of GPC3 mRNA and protein was evident in tumor cells from >80% of patients with melanoma and melanocytic nevus, which is a common benign lesion. GPC3 protein was detected in sera from 40% (36/91) of melanoma patients, but not in sera from those with large congenital melanocytic nevus, or from healthy donors. Surprisingly, we detected serum GPC3 even in patients with stage 0, in situ melanoma. The positive detection rate of serum GPC3 at stage 0, I, and II (44.4%, 40.0%, 47.6%, respectively) was significantly higher than that of 5-S-cysteinyldopa, a well known tumor marker for melanoma (0.0%, 8.0%, and 10.0%, respectively). Interestingly, GPC3 was highly immunogenic in mice and elicited effective anti-tumor immunity with no evidence of autoimmunity. Thus, GPC3 is useful for diagnosis of HCC and melanoma and may also have a role in immunotherapy or tumor prevention. However, studies in humans are warranted.

Animals↗
PubMedDate not supplied

[Current biological markers of cutaneous melanoma progression].

Melanoma is the most agressive skin cancer in humans. The most important prognostic factors are the histological features of the tumor, while the clinical ones play a secondary role. Melanoma progression is characterized by the metastatic process which directly threatens the patients life. Unfortunately, routine imaging methods cannot estimate early enough this metastatic risk. Are biologic markers of cancer progression more efficient than those applied in everyday practice? Are they able to evaluate the metastatic risk and thus help the therapeutic strategy? In this review, we analysed the analytical and the clinical aspects of biologic markers of cutaneous melanoma currently available or in development. At the present time it is very difficult to distinguish one single marker of melanoma progression in the blood which correlates with the stage and the prognosis of melanoma. The most specific and sensitive enough are the melanoma associated antigens protein S-100, MIA (melanoma inhibiting activity) and the melanin precursors 5-S-cysteinyldopa and the ratio L-dopa/L-tyrosine. Tyrosinase mRNA remains the best target for the detection of circulating metastatic melanoma cells by RT-PCR. Simultaneous detection of several markers might be useful if they are carefully selected. Despite the progress in the field, more clinical studies should be performed for the development of new techniques or improvements of the existing ones for the follow-up of cutaneous melanoma.

Antigens, Neoplasm↗
PubMed1992

Spitz naevus of the toe.

A 68-year-old Japanese woman presented with a brownish macule, containing two papules, on her left fourth toe. Histological examination revealed an intradermal epithelioid cell tumour with irregularly shaped, bizarre giant cells. In the upper portion of the tumour, the epithelioid cells contained abundant melanin. A low amount of 5-S-cysteinyldopa and a diploid DNA distribution histographic pattern were helpful in differentiating the lesion from malignant melanoma. This location of a Spitz naevus is exceptional.

Aged↗