cysteinyldopa and 6-hydroxy-5-methoxy-2-indolylcarboxylic-acid

Topics: Animals; Biomarkers, Tumor; Cysteinyldopa; Humans; Indoles; Melanoma; Skin Neoplasms

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.

Topics: Cysteinyldopa; Humans; Hypoxia; Indoles; Melanocytes; PUVA Therapy; Skin Pigmentation; Ultraviolet Rays

Different wavelengths of ultraviolet (UV) radiation elicit different responses in the skin. UVA induces immediate tanning and persistent pigment darkening through oxidation of pre-existing melanin or melanogenic precursors, while UVB induces delayed tanning which takes several days or longer to develop and requires activation of melanocytes. We compared the effects of a 2-week repetitive exposure of human skin to solar-simulated radiation (SSR), UVA or UVB at doses eliciting comparable levels of visible tanning and measured levels of melanins and melanin-related metabolites. Levels of eumelanin and pheomelanin were significantly higher in the order of SSR, UVB, UVA or unexposed control skin. Levels of free 5-S-cysteinyldopa (5SCD) were elevated about 4-fold in SSR- or UVB-exposed skin compared with UVA-exposed or control skin. Levels of protein-bound form of 5SCD tended to be higher in SSR- or UVB-exposed skin than in UVA-exposed or control skin. Total levels of 5-hydroxy-6-methoxyindole-2-carboxylic acid (5H6MI2C) and 6H5MI2C were higher in SSR- than in UVB-exposed or control skin. These results show that SSR is more effective in promoting delayed tanning than UVB radiation alone, suggesting a synergistic effect of UVA radiation. Furthermore, free 5SCD may serve as a good marker of the effect of SSR and UVB.

Topics: Adult; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Indoles; Male; Melanins; Middle Aged; Radiation Dosage; Skin; Skin Pigmentation; Sunlight; Ultraviolet Rays

Ultraviolet-B (UVB) radiation due sunlight can result in sunburns and/or suntans. Sunburn occurs only several hours after solar UVB radiation, while a suntan requires several days to several weeks to develop. In the present study, we measured serum and urine levels of melanin-related metabolites, 5-S-cysteinyldopa (5-S-CD) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C), in nine subjects exposed to normal sunlight over the course of 12 months. We collected samples in the middle of each month and examined the variation of the markers, the correlation between them, and their correlation with solar UVB radiation. Those markers exhibited a seasonal variation with lower values in the winter and higher values in the summer. Levels of 5-S-CD and 6H5MI2C in the serum showed 48% and 54% increases in the summer compared with those in the winter, respectively. Comparison of 5-S-CD in the serum and urine showed the highest correlation (r2 = 0.344), followed by the pair of 5-S-CD and 6H5MI2C in the serum. Levels of 5-S-CD in the serum showed the highest correlation (r2 = 0.729) with the mean solar UVB radiation during the first 10 d of the month, while 6H5MI2C in the serum was highly correlated (r2 = 0.483) with solar UVB radiation during the previous month. Levels of 5-S-CD and 6H5MI2C in the serum appear to reflect the degrees of skin injury and pigmentation in the skin, respectively.

Topics: Adult; Biomarkers; Cysteinyldopa; Female; Humans; Indoles; Male; Melanins; Middle Aged; Seasons; Skin; Skin Pigmentation; Ultraviolet Rays

In a series of 92 patients with malignant melanoma, clinical stage III or IV, both 5-S-cysteinyldopa (5SCD) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) were measured in urine during chemotherapy. A total of 434 urine specimens were analysed. The sensitivity of 5SCD for the detection of stage III-IV melanoma was 83%, while the corresponding sensitivity of 6H5MI2C was 52%. Fifty per cent of patients with one metastatic site had increased 5SCD excretion, while all patients with four or more metastatic sites had increased excretion. A significant correlation was found between 5SCD decrease and clinical regression (P<0.001) and between 5SCD increase and clinical progression (P<0.001). Corresponding correlations were not found for 6H5MI2C. Increments in 5SCD excretion (median 269 micromol/mol creatinine) were seen for 83% of the occasions when clinical progression was recorded, and decrements in 5SCD excretion (median 145 micromol/mol creatinine) were seen for 85% of the occasions when clinical regression was seen. During clinical 'stable disease' increases in 5SCD excretion were seen in 59% and decreases in 41%. The median value of 5SCD changes for stable disease was 7.0 micromol/mol creatinine, indicating a chemical marker stability in many cases. We recommend the use of 5SCD in urine as a valuable, reliable and simple biochemical marker to use in the clinical follow-up of melanoma patients with advanced disease.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cysteinyldopa; Disease Progression; Female; Follow-Up Studies; Humans; Indoles; Male; Melanoma; Middle Aged; Skin Neoplasms

Elevated levels of the phaeomelanin metabolite 5-S-cysteinyldopa and the eumelanin metabolite 6-hydroxy-5-methoxyindole-2-carboxylic acid in urine and serum have been shown in previous studies to correlate with disseminated malignant melanoma. Immunohistochemical detection of S100B protein is an acknowledged method for the diagnosis of malignant melanoma, and it has been suggested that rising serum levels of S100B protein are associated with the survival rate of patients with malignant melanoma. In the present study serum levels of S100B protein and urinary concentrations of 5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid were measured in 91 patients with histopathologically verified malignant melanoma. At the time of sampling 13 patients were in clinical stage I, 13 in stage II and 65 in stage III. The urinary levels of the melanin metabolites were determined by automated high performance liquid chromatography, and the serum levels of S100B protein by an immunoradiometric assay with two monoclonal antibodies. The overall survival rate was most strongly associated with the serum levels of S100B protein (P < 0.001), but there was also a significant correlation to urinary levels of 5-S-cysteinyldopa (P < 0.001). A corresponding association with urinary levels of 6-hydroxy-5-methoxyindole-2-carboxylic acid was found in only a very few patients with extremely high urinary concentrations. A statistically significant increase in relative hazard was found for S100B protein levels exceeding 0.6 microgram/l (P < 0.001), and predictably for patients in clinical stage III (P < 0.001). An analysis of S100B protein levels in patients in clinical stage III showed a significant correlation to survival (P = 0.005). Our study suggests that of the three biochemical tumour markers, S100B and to a lesser extent 5-S-cysteinyldopa have the greatest potential to be used as predictors of survival prognosis in patients with malignant melanoma.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Autoantigens; Biomarkers, Tumor; Calcium-Binding Proteins; Cysteinyldopa; Disease-Free Survival; Female; Humans; Indoles; Male; Melanoma; Middle Aged; Neoplasm Invasiveness; Nerve Growth Factors; Prognosis; Radioimmunoassay; Regression Analysis; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Skin Neoplasms; Survival Rate; Time Factors

Serum concentrations of 5-S-cysteinyldopa (5-S-CD) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) have been used as biochemical markers of melanoma progression. We examined the effect of solar radiation on serum levels of 5-S-CD and 6H5MI2C in 10 healthy Japanese by measuring these markers every month during a period of 2 years. 5-S-CD levels were higher in early summer and lower in early winter. The difference in the average levels was approximately twofold, but among the 240 samples, no individual values exceeded the upper limit of normal value, 10 nmol/L. A significant correlation (P < 0.02) was observed between 5-S-CD level and solar radiation. 6H5MI2C levels showed a smaller variation than 5-S-CD. No correlation was observed between 6H5MI2C level and solar radiation. This study showed that serum 5-S-CD and 6H5MI2C in healthy Japanese did not exceed the upper limit of normal values even in sunny season.

Topics: Cysteinyldopa; Indoles; Japan; Reference Values; Seasons; Sunlight

5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid are important intermediate metabolites in the formation of cutaneous melanin pigment. Since they both are serious candidates as markers of melanoma progression, their stability in urine has been investigated during storage at various conditions. The results show that storage at -20 degrees C is necessary. Both compounds are nonstable at room temperature, particularly if the urine was not acidified to pH 4-5. Reference levels were obtained from analysis of urine from 31 men and 40 women. The mean (SD) excretion of 5-S-cysteinyldopa was 32 (12.5) mumol/mol creatinine (women). Corresponding figures for 6H5MI2C were 23 (10.3) and 24 (8.1) mumol/mol creatinine for men and women respectively.

Topics: Adult; Body Weight; Creatinine; Cysteinyldopa; Female; Humans; Hydrogen-Ion Concentration; Indoles; Male; Reference Values

This article introduces a rapid high-performance liquid chromatographic assay to measure urinary pheomelanin and eumelanin metabolites, 5-S-cysteinyldopa and indoles, 5(6)-hydroxy-6(5)-methoxyindole-2-carboxylic acid.. Our high-performance liquid chromatographic study clearly showed (1) urine of melanoma patients with positive metastasis revealed significant amounts of 5-S-cysteinyldopa and indoles (5,6-dihydroxyindole-2-carboxylic acid plus 6-hydroxy-5-methoxyindole-2-carboxylic acid) above 1 mumol/d and 2 mumol/d, respectively; and (2) in patients with metastasis-free melanoma these melanin metabolites might be excreted into the urine but always less than the two values cited above.. As there is a discrepancy regarding the specificity of 5-S-cysteinyldopa as a marker for estimation of melanoma metastasis, high-performance liquid chromatographic measurement of urinary indoles will provide an additional assay in the detection of melanoma metastasis from an early stage. Both melanoma markers were increased in the urine of patients with metastatic melanoma.

Topics: Adult; Biomarkers, Tumor; Cysteinyldopa; Humans; Indoles; Male; Melanoma; Middle Aged; Skin Neoplasms

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.

Topics: Animals; Biomarkers, Tumor; Cysteinyldopa; Dihydroxyphenylalanine; Dopamine; Indoles; Melanins; Melanoma, Experimental; Mice; Mice, Inbred C57BL

The melanocyte activity was studied by analysis of the urinary excretion of indolic and cysteinyldopa compounds. One eumelanin marker, 5,6-dihydroxy-indole-2-carboxylic acid was identified and quantified in normal urine. However, its low concentration and sensitivity to oxidation made it less suitable for clinical studies. A methylated derivative of this substance, 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI-2-C), was also demonstrated in normal urine. A quantitative method was worked out and the normal urinary concentration of this substance was as high as the concentration of 5-S-cysteinyldopa. The concentrations of the eumelanic marker 6-hydroxy-5-methoxyindole-2-carboxylic acid and the pheomelanic marker 5-S-cysteinyldopa were determined in the urine of psoriasis patients during PUVA treatment and also in the urine of subjects with different skin colour. The melanocyte activity in albinotic patients and in albinotic mice was studied by the same technique. Some in vitro experiments were performed to show that 5-S-glutathionyldopa has the molecular properties of forming a mercapto-substituted indole derivative. The following main conclusions were drawn: 1. 5,6-Dihydroxyindole-2-carboxylic acid and 6-hydroxy-5-methoxyindole-2-carboxylic acid are both present in measurable amounts in normal urine. 2. The urinary concentration of 6-hydroxy-5-methoxyindole-2-carboxylic acid increased during PUVA treatment in a similar way as for 5-S-cysteinyldopa. 3. The eumelanic marker 6-hydroxy-5-methoxyindole-2-carboxylic acid was excreted in larger quantities by people with genetically dark skin, whereas the pheomelanic marker 5-S-cysteinyldopa was not related to pigment type. 4. In the urine of one albino patient and in the urine of albinotic mice a total absence of 6-hydroxy-5-methoxyindole-2-carboxylic acid was found. The urinary concentrations of 5-S-cysteinyldopa in these subjects were measurable but lower than in pigmented subjects. Thus, 6-hydroxy-5-methoxy-indole-2-carboxylic acid seems to be a more specific melanocyte marker than the cysteinyldopas.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Albinism; Animals; Biomarkers; Cysteinyldopa; Humans; Indoles; Melanocytes; Mice; Oxidation-Reduction; Pigmentation; PUVA Therapy

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.

Topics: Adult; Aged; Cysteinyldopa; Female; Humans; Indoles; Male; Melanoma; Melanosis; Microscopy, Electron; Skin Neoplasms; Thiazines

The urinary excretion of 2 melanocyte metabolites was studied in normal people of different skin type. The sulphur-free indole derivative 6-hydroxy-5-methoxyindole-2-carboxylic acid was excreted in larger quantities by people with genetically dark skin, whereas the excretion of 5-S-cysteinyldopa was not related to pigment type. No correlation between 5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid excretion emerged.

Topics: Adult; Black People; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Indoles; Male; Melanins; Melanocytes; Skin Pigmentation; White People

The urine of an albino woman contained small quantities of 5-S-cysteinyldopa; 6-hydroxy-5-methoxyindole-2-carboxylic acid, a melanin precursor metabolite, was lacking. The 5-S-cysteinyldopa excretion observed may reflect non-specific oxidation of dopa. Two other albino patients showed normal values for the excretion of 5-S-cysteinyldopa and of 6-hydroxy-5-methoxyindole-2-carboxylic acid.

Topics: Adult; Albinism; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Indoles; Osmolar Concentration; Oxidation-Reduction

Urinary excretion of the phaeomelanin precursor 5-S-cysteinyldopa (5-S-CD) and the eumelanin metabolite 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI-2-C) was studied in black and albino mice. The urinary concentration of 5-S-CD was 31.7 ng/ml in black and 16.1 ng/ml in albino mice. The concentration of 6H5MI-2-C was 21.0 ng/ml in the urine of black mice. The compound could not be demonstrated in the urine of albino mice.

Topics: Albinism; Animals; Cysteinyldopa; Female; Indoles; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Reference Values

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.

Topics: Adult; Contraceptives, Oral; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Indoles; Melanoma; Menstruation; Pregnancy; Skin Pigmentation

The urinary excretion of the eumelanin metabolite 6-hydroxy-5-methoxyindole-2-carboxylic acid and the pheomelanin metabolite 5-S-cysteinyldopa was followed during PUVA treatment for 6 weeks. They showed similar excretion patterns, with the highest values within 1-2 wk.

Topics: Adult; Cysteinyldopa; Dihydroxyphenylalanine; Female; Humans; Indoles; Kinetics; Male; Middle Aged; Photochemotherapy; Psoriasis; PUVA Therapy