Cysteinyldopa isomers and dopa in lesions and urine of Japanese patients with malignant melanoma

Morishima, Takafumi; Tatsumi, Fumiko; E, Fukada; Saito, Mariko; Fujita, Mitsue; Nagashima, Noriyasu; Hanawa, Satoshi

doi:10.1007/bf00412878

Cited by 28 publications

(11 citation statements)

References 15 publications

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“…The pheomelanogenesis pathway proposed was supported by the identification of 5‐ S ‐CD (54) and other isomers, along with the diadduct, in the urine of melanoma patients (55). The ratios between various isomers of cysteinyldopa found in melanoma urine and tissues (56) are similar to those obtained by incubation of dopa with tyrosinase in vitro in the presence of cysteine (38), which suggests that cysteinyldopas originate in vivo by a similar route involving the addition of cysteine to dopaquinone.…”

Section: Current Concepts Of Melanogenesismentioning

confidence: 93%

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone^†

Ito¹,

Wakamatsu

2007

Photochem & Photobiology

413

463

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Melanins can be classified into two major groups-insoluble brown to black pigments termed eumelanin and alkali-soluble yellow to reddish-brown pigments termed pheomelanin. Both types of pigment derive from the common precursor dopaquinone (ortho-quinone of 3,4-dihydroxyphenylalanine) which is formed via the oxidation of L-tyrosine by the melanogenic enzyme tyrosinase. Dopaquinone is a highly reactive ortho-quinone that plays pivotal roles in the chemical control of melanogenesis. In the absence of sulfhydryl compounds, dopaquinone undergoes intramolecular cyclization to form cyclodopa, which is then rapidly oxidized by a redox reaction with dopaquinone to give dopachrome (and dopa). Dopachrome then gradually and spontaneously rearranges to form 5,6-dihydroxyindole and to a lesser extent 5,6-dihydroxyindole-2-carboxylic acid, the ratio of which is determined by a distinct melanogenic enzyme termed dopachrome tautomerase (tyrosinase-related protein-2). Oxidation and subsequent polymerization of these dihydroxyindoles leads to the production of eumelanin. However, when cysteine is present, this process gives rise preferentially to the production of cysteinyldopa isomers. Cysteinyldopas are subsequently oxidized through redox reaction with dopaquinone to form cysteinyldopaquinones that eventually lead to the production of pheomelanin. Pulse radiolysis studies of early stages of melanogenesis (involving dopaquinone and cysteine) indicate that mixed melanogenesis proceeds in three distinct stages-the initial production of cysteinyldopas, followed by their oxidation to produce pheomelanin, followed finally by the production of eumelanin. Based on these data, a casing model of mixed melanogenesis is proposed in which a preformed pheomelanic core is covered by a eumelanic surface.

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Section: Current Concepts Of Melanogenesismentioning

confidence: 93%

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone^†

Ito¹,

Wakamatsu

2007

Photochem & Photobiology

413

463

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“…In previous reports from our laboratory, the HPLC conditions used were such that AHP and 3‐aminotyrosine (AT) eluted in a single peak. This was based on the assumption that any natural pheomelanin pigment consists of a fixed ratio of 5‐ S ‐CD and 2‐ S ‐CD because the ratio of these CD isomers in biological materials is chemically controlled to be approximately 5:1 (30, 31). In fact, the estimation of pheomelanin as the combined amount of AHP and AT (in this report, we call this combined amount `total' AHP to discriminate from `specific' AHP) did not impose any serious problem in most cases.…”

Section: ‐Amino‐3‐hydroxyphenylalanine (Ahp) As a Specific Marker Ofmentioning

confidence: 99%

Advanced Chemical Methods in Melanin Determination

Wakamatsu¹,

Ito²

2002

Pigment Cell Research

301

274

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Among the biopolymers, melanins are unique in many respects. The other essential biopolymers -proteins, nucleic acids, and carbohydrates -are chemically well characterized; their precursors (monomer units) and modes of connection between the monomer units are known, and sequences of their connection can be determined with well-established methodologies. In contrast, we still do not have a method to determine accurately the ratio of various units present in melanins. This is largely because of the chemical properties of melanins, such as their insolubility over a broad range of pH, the heterogeneity in their structural features, and also because of the lack of methods that can split melanin polymers into their monomer units (all other biopolymers can be hydrolysed to the corresponding monomer units). To overcome this difficulty, we developed a rapid and sensitive method for quantitatively analysing eumelanin and pheomelanin in biological samples by chemical degradation methods followed by HPLC determination. This HPLC microanalytical method for characterizing eumelanin and pheomelanin has become a useful tool for the study of melanogenesis. This review will summarize the usefulness and limitations of the various chemical and spectrophotometric methods used to analyse melanins at the biochemical, cellular, and tissue levels. Emphasis is given on the usefulness of 4-amino-3-hydroxyphenylalanine as a specific marker of pheomelanin.

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“…Addition of cysteine to dopaquinone. Relative isomeric distribution found in urine from melanoma patients and in melanoma tissue: 2SCD-l0%, 5SCD--80%, 6SCD-3%, and DCD-7% (Morishima et al, 1983). cysteine and tyrosinase-generated dopaquinone the chemical synthesis and characterization of the major product of this reaction, SSCD (Prota et a!., 1968), has led to rapid advancements in pheomelanin chemistry and melanocyte biochemistry.…”

Section: Dcdmentioning

confidence: 99%

PHOTOCHEMISTRY and PHOTOBIOLOGY OF MELANOGENIC METABOLITES: FORMATION OF FREE RADICALS*

Koch

Chedekel

1987

Photochem & Photobiology

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Normal melanocytes produce specialized subcellular organelles called melanosomes within which the biochemical processes of melanogenesis occurs. During sunlight‐induced melanogenesis, the melanocyte‐specific enzyme tyrosinase catalyzes the oxidative polymerization of 3,4‐dihydroxyphenyl‐alanine (DOPA) to melanin. Nucleophilic addition of cysteine to tyrosinase‐generated dopaquinone leads to the formation of cysteinyldopas, precursors of pheomelanin and excreted by‐products of eumelanogenesis. Under conditions of low sulfhydryl content, dopaquinone undergoes a 1,4 intramolecular cycloaddition to yield, after further oxidation, 5,6‐dihydroxyindoles and/or 5,6‐dihydroxy‐2‐carboxyindoles. These indolic melanogenic intermediates and their O‐methylated metabolites, like cysteinyldopas, are excreted by actively pigmenting as well as dormant melanocytes. Indeed, it has been determined that in humans, the serum and urine concentrations of these melanogenic metabolites increase dramatically following exposure to sunlight, UVA (315‐400 nm), UVB (290‐315 nm) exposure, as well as during PUVA therapy and in melanoma patients, and thus have proved to be excellent biochemical markers of normal and pathological melanocyte function. While controlled light exposure or PUVA therapy generally lead to 100‐300% increases in 5‐S‐cysteinyldopa (5SCD) and 5‐methoxy‐6‐hydroxyindole‐2‐carboxylic acid (6HMICA) serum levels (normal concentration about 4–16 nmol l‐1), the local concentrations in the skin and especially in the actively pigmenting melanocyte may be as high as 200 μM. Evidence is presented to document that a number of catecholic melanin precursors, including cysteinyldopas and dihydroxyindoles, are photochemically unstable in the presence of biologically relevant ultraviolet radiation (i.e. wavelengths ± 300 nm). Initial photochemical processes involve free radical production; continued photolysis yields polymeric photoproducts. Radicals produced during melanogenic metabolite photolysis have been identified by ESR spin trapping, laser flash photolysis and pulse radiolysis techniques and include hydrated electrons (eaq), hydrogen atoms (H'), hydroxyl radicals (OH), semiquinones, aryl thiyl (ArS), and alanyl carbon‐based radicals. In vitro investigations of the potential photobiological significance of these reactions have demonstrated photolysis of cysteinyldopas may lead to photoinitiated DNA binding and single strand break induction. The above mentioned radical species may also damage proteins and initiate lipid peroxidation. Definitive evidence for the occurrence of these phototoxic reactions in vivo is currently unavailable, however our in vitro studies suggest a possible role for melanogenic metabolite photolysis in acute and chronic solar responses of human skin.

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Cysteinyldopa isomers and dopa in lesions and urine of Japanese patients with malignant melanoma

Cited by 28 publications

References 15 publications

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone^†

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone^†

Advanced Chemical Methods in Melanin Determination

PHOTOCHEMISTRY and PHOTOBIOLOGY OF MELANOGENIC METABOLITES: FORMATION OF FREE RADICALS*

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Cysteinyldopa isomers and dopa in lesions and urine of Japanese patients with malignant melanoma

Cited by 28 publications

References 15 publications

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone†

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone†

Advanced Chemical Methods in Melanin Determination

PHOTOCHEMISTRY and PHOTOBIOLOGY OF MELANOGENIC METABOLITES: FORMATION OF FREE RADICALS*

Contact Info

Product

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Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone^†

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone^†