Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.10.3.1 (tyrosinase)
 9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanin contains melanin-free radicals and can both absorb and produce additional free radicals and active oxygen species on exposure to various stimuli. Yet its role in the radiation responses of malignant melanoma has been little studied. In this report, three subclones of Cloudman S91 mouse melanoma clone PC1A varying in constitutive melanin content were compared with respect to killing by gamma irradiation. Radiation responses correlated with melanin content. The least melanotic line, S91/amel, was most sensitive and the most melanotic line, S91/I3, was most resistant. Curve fitting using the linear-quadratic model suggests that S91/amel is killed only by single event inactivations; S91/I3, only by double event inactivations; and S91/M1B, with intermediate melanin and radiation response, by both types of inactivations. Split dose experiments confirmed a lack of immediate split dose recovery in S91/amel and its existence in S91/I3. Potentially lethal damage and its repair could be demonstrated in both S91/amel and S91/I3. Double strand break (DSB) induction was evaluated as a function of gamma ray dose in DNA of S91/I3 and S91/amel, as well as in EMT6, a mouse mammary cancer line that lacks tyrosinase and melanin. The rates of induction were proportional to cellular melanization, i.e., the rate of DSB induction was greatest in S91/I3, least in EMT6. Levels of thioredoxin reductase (TR), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT) were determined in S91/amel and S91/I3. TR was the same in both cell lines, while the other three enzymes were 3- to 4-fold lower in S91/amel.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does melanin affect the low LET radiation response of Cloudman S91 mouse melanoma cell lines? 194 13

Azelaic acid, and other saturated dicarboxylic acids (C9-C12), are shown to be competitive inhibitors of tyrosinase (KI azelaic acid = 2.73 X 10(-3) M) and of membrane-associated thioredoxin reductase (KI azelaic acid = 1.25 X 10(-5) M). The monomethyl ester of azelaic acid does not inhibit thioredoxin reductase, but it does inhibit tyrosinase, although double the concentration is necessary compared with azelaic acid (KI azelaic acid monomethyl ester = 5.24 X 10(-3) M). Neither azelaic acid nor its monomethyl ester inhibit tyrosinase when catechol is used as a substrate instead of L-tyrosine. Therefore, the weak inhibitory action of azelaic acid on tyrosinase appears to be due to the competition of a single carboxylate group on this inhibitor for the alpha-carboxylate binding site of the L-tyrosine substrate on the enzyme active site. Based on the inhibitor constant on tyrosinase, at least cytotoxic levels of azelaic acid would be required for the direct inhibition of melanin biosynthesis in melanosomes if this mechanism is responsible for depigmentation in the hyperpigmentation disorders lentigo maligna and melasma. Alternatively only 10(-5) M azelaic acid is required to inhibit thioredoxin reductase. This enzyme is shown to regulate tyrosinase through a feedback mechanism involving electron transfer to intracellular thioredoxin, followed by a specific interaction between reduced thioredoxin and tyrosinase. Furthermore, the thioredoxin reductase/thioredoxin system is shown to be a principal electron donor for the ribonucleotide reductases which regulates DNA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A possible mechanism of action for azelaic acid in the human epidermis. 211 32

A study of guinea pig and human skin in vivo has revealed that keratinocytes contain a thioenzyme which reduces radicals. This enzyme has been purified by affinity column chromatography and identified as thioredoxin reductase. In vivo and in vitro bioassays were performed by using a spin-labelled surfactant as the radical substrate, because it can diffuse through the stratum corneum and react by surface complexation with the epidermis and also on the outer plasma membrane of keratinocytes from cell cultures. Thioredoxin, the native substrate for thioredoxin reductase effectively competes for electrons with radical substrates. Nicotinamide adenine dinucleotide phosphate (NADPH) is the electron donating coenzyme in both the reduction of radicals and thioredoxin. Reduced thioredoxin has been shown to be an inhibitor of tyrosinase, whereas oxidized thioredoxin has no effect on this enzyme activity. Taken together these results indicate that the thioredoxin/thioredoxin reductase system plays an important role in preventing cell damage from UV-generated free radicals on the skin.
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PMID:The role of thioredoxin reductase in the reduction of free radicals at the surface of the epidermis. 242 87

Medium chain length dicarboxylic acids (DA) from C8 to C13 are competitive inhibitors of tyrosinase in vitro. The introduction of electron acceptor groups or electron donor groups into the 2 and/or the 8 position of the molecule enhances or reduces respectively the inhibitory effects of DA. In addition to tyrosinase, DA can reversibly inhibit thioredoxin reductase, NADPH cytochrome P450 reductase, NADH dehydrogenase, succinic dehydrogenase and H2CoQ-Cytochrome C oxidoreductase. Among DA, azelaic acid (AA, C9 dicarboxylic acid) is extensively used because: 1) it is much cheaper than other DA; 2) it has no apparent toxic or teratogenic or mutagenic effect; 3) when administered perorally to humans, at the same concentrations as the other DA, it reaches much higher serum and urinary concentrations. Serum concentrations and urinary excretion obtained with intravenous or intra-arterial infusions of AA are significantly higher than those achievable by oral administration. Together with AA, variable amounts of its catabolites, mainly pimelic acid, are found in serum and urine, indicating an involvement of mitochondrial beta-oxidative enzymes. Short-lived serum levels of AA follow a single 1 h intravenous infusion, but prolonging the period of infusion with successive doses of similar concentration produces sustained higher levels during the period of administration. These levels are consistent with the concentrations of AA capable of producing a cytotoxic effect on tumoral cells in vitro. AA is capable of crossing the blood-brain barrier: its concentration in the cerebrospinal fluid is normally in the range of 2-5% of the values in the serum.
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PMID:Azelaic acid--biochemistry and metabolism. 250 63

Hermansky-Pudlak syndrome is a hereditary disease with an autosomal recessive mode of inheritance, characterized by the triad of tyrosinase-positive oculocutaneous albinism, a hemorrhagic diathesis resulting from storage pool-deficient platelets, and accumulation of ceroid/lipofuscin-like material in various cells and tissues and in the urine. The basic defect in this syndrome remains unknown. It is believed that the primary defect may involve membranes of the platelet-dense bodies and the melanosomes. Recently a defective calcium uptake system and low activities for membrane-associated thioredoxin reductase have been shown in Hermansky-Pudlak syndrome, and their possible role in the pathomechanism of this disorder is discussed.
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PMID:[Hermansky-Pudlak syndrome]. 265 78

The human epidermis presents the first line of defense against invading free radicals. Therefore, the surface of the skin must be equipped to deal with both the penetration of ultra-violet light as well as the neutralization of reactive photochemical products such as superoxide anion radical, hydrogen peroxide and especially hydroxyl radicals. Consequently, the human epidermis contains a variety of anti-oxidants to reduce oxygen radicals and hydrogen peroxide. The photochemical production of hydroxyl radicals, from both extracellular and intracellular hydrogen peroxide, is of special significance to the integrity of cells in the human epidermis. Recently, both biochemical and clinical studies on the healthy human population, and on patients with pigmentation disorders, suggested a connection between free radical defense by plasma membrane associated thioredoxin reductase and melanin biosynthesis. This research provided the first evidence for a direct relationship between free radical concentration and pigmentation. Furthermore, this system has been shown to be regulated by both extracellular and intracellular calcium concentrations. Clinical studies show depigmentation disorders vitiligo and tyrosinase positive albinism (Hermansky-Pudlak syndrome) appear to have defective calcium uptake systems influencing both free radical defense and melanin biosynthesis.
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PMID:Free radical reduction in the human epidermis. 266 65

Recent studies indicate that membrane-associated thioredoxin reductase (TR) is a possible regulator of melanin biosynthesis via the inhibition of tyrosinase by reduced thioredoxin. In normal individuals, the levels of TR activity in skin correlate linearly to the Fitzpatrick classification of skin type, being lowest in type I skin and highest in skin type VI. In this study, TR was measured in 3-mm skin biopsies in Hermansky-Pudlak syndrome (HPS) patients and their relatives. Forty-five individuals from seven Puerto Rican kindreds were tested, including 12 homozygotes, nine obligate heterozygotes, and 24 unclassified individuals. In addition, seven separate nonkindred HPS patients were tested. With one exception, TR activity was markedly decreased in 18 homozygotes. TR activity was decreased in eight obligate heterozygotes and in 12 unclassified kindred members, whereas 10 subjects had normal TR activity when compared to the expected activity of their skin type. Four individuals were excluded from the analysis because of inadequate controls for their age group or immunosuppressive treatment for kidney transplant. The results indicate that decreased TR activity assayed in 3-mm skin punch biopsies is a useful method for detecting carriers of the HPS gene.
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PMID:Thioredoxin reductase activity in Hermansky-Pudlak syndrome: a method for identification of putative heterozygotes. 334 59

X-rays were used to induce melanin biosynthesis in brown and black guinea pigs in vivo. During the course of pigmentation, the expression of thioredoxin reductase was increased, whereas for the other antioxidant enzymes, superoxide dismutase (cytosol Cu/Zn-enzyme), catalase, and glutathione reductase, levels and activities decreased. Isobutylmethylxanthine induced eumelanin biosynthesis in murine melanoma cells (Cloudman S-91). In these cells, thioredoxin reductase levels coincided with melanogenesis. Our results suggest that both tyrosinase and thioredoxin reductase respond to oxidative stress in the epidermis as well as in melanoma cells and react with superoxide anion radicals to stimulate melanogenesis and to prevent peroxidative damage, respectively.
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PMID:Thioredoxin reductase induction coincides with melanin biosynthesis in brown and black guinea pigs and in murine melanoma cells. 752 41

(6R)5,6,7,8 tetrahydrobiopterin (6-BH4) is an important cofactor in the regulation of melanogenesis in melanocytes, where it controls: (a) the supply of L-tyrosine from L-phenylalanine via phenylalanine hydroxylase, and (b) regulates directly dopaquinone formation from L-tyrosine via tyrosinase. 6-BH4 undergoes redox-cycling by its oxidation to quinonoid dihydrobiopterin (qBH2) and to 6-biopterin through consecutive two electron oxidation reactions. The oxidized cofactor 6-biopterin (0.2 x 10(-6) M) is extremely cytotoxic to human melanocytes under in vitro conditions. Consequently, its reduction to 6-BH4 via q-BH2 is essential to melanocyte viability. In addition, the results herein show for the first time that human thioredoxin reductase has the capacity to reduce 6-biopterin to q-BH2 where further reduction to 6-BH4 follows via dihydropteridine reductase or reduced glutathione.
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PMID:Cytotoxicity of 6-biopterin to human melanocytes. 794 90