Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione is an ubiquitous compound found in our bodies. Aside from its many ascribed biologic functions, it has also been implicated in skin lightening. We review in vitro and in vivo studies that show evidence of its involvement in the melanogenic pathway and shed light on the its anti-melanogenic effect. Proposed mechanisms of action include: (a) direct inactivation of the enzyme tyrosinase by binding with the copper-containing active site of the enzyme; (b) mediating the switch mechanism from eumelanin to phaeomelanin production; (c) quenching of free radicals and peroxides that contribute to tyrosinase activation and melanin formation; and d) modulation of depigmenting abilities of melanocytotoxic agents. These concepts supported by the various experimental evidence presented form basis for future research in the use of glutathione in the treatment of pigmentary disorders.
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PMID:Glutathione as a depigmenting agent: an overview. 1849 81

Glutathione dose dependently inhibited melanin synthesis in the reaction of tyrosinase and L-DOPA. The inhibition of melanin synthesis was recovered by increasing the concentration of L-DOPA, but not recovered by increasing tyrosinase. Glutathione inhibited the binding between tyrosinase and L-DOPA. Although the synthesized melanin was aggregated within 1 h, the aggregation was inhibited by the addition of glutathione. These results indicate that glutathione inhibits the synthesis and agglutination of melanin by interrupting the function of L-DOPA.
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PMID:[Inhibitory mechanism of melanin synthesis by glutathione]. 1867 Jan 86

In this work, we investigated the biochemical mechanism of acetaminophen (APAP) induced toxicity in SK-MEL-28 melanoma cells using tyrosinase enzyme as a molecular cancer therapeutic target. Our results showed that APAP was metabolized 87% by tyrosinase at 2 h incubation. AA and NADH, quinone reducing agents, were significantly depleted during APAP oxidation by tyrosinase. The IC(50) (48 h) of APAP towards SK-MEL-28, MeWo, SK-MEL-5, B16-F0, and B16-F10 melanoma cells was 100 microM whereas it showed no significant toxicity towards BJ, Saos-2, SW-620, and PC-3 nonmelanoma cells, demonstrating selective toxicity towards melanoma cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, enhanced APAP toxicity towards SK-MEL-28 cells. AA and GSH were effective in preventing APAP induced melanoma cell toxicity. Trifluoperazine and cyclosporin A, inhibitors of permeability transition pore in mitochondria, significantly prevented APAP melanoma cell toxicity. APAP caused time and dose-dependent decline in intracellular GSH content in SK-MEL-28, which preceded cell toxicity. APAP led to ROS formation in SK-MEL-28 cells which was exacerbated by dicoumarol and 1-bromoheptane whereas cyslosporin A and trifluoperazine prevented it. Our investigation suggests that APAP is a tyrosinase substrate, and that intracellular GSH depletion, ROS formation and induced mitochondrial toxicity contributed towards APAP's selective toxicity in SK-MEL-28 cells.
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PMID:Biochemical mechanism of acetaminophen (APAP) induced toxicity in melanoma cell lines. 1875 48

In the current work, we investigated the biochemical toxicity of acetylsalicylic acid (ASA; Aspirin) in human melanoma cell lines using tyrosinase enzyme as a molecular cancer therapeutic target. At 2 h, ASA was oxidized 88% by tyrosinase. Ascorbic acid and NADH, quinone reducing agents, were significantly depleted during the enzymatic oxidation of ASA by tyrosinase to quinone. The 50% inhibitory concentration (48 h) of ASA and salicylic acid toward SK-MEL-28 cells were 100 micromol/l and 5.2 mmol/l, respectively. ASA at 100 micromol/l was selectively toxic toward human melanocytic SK-MEL-28, MeWo, and SK-MEL-5 and murine melanocytic B16-F0 and B16-F10 melanoma cell lines. However, ASA was not significantly toxic to human amelanotic C32 melanoma cell line, which does not express tyrosinase enzyme, and human nonmelanoma BJ, SW-620, Saos, and PC-3 cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, increased ASA toxicity toward SK-MEL-28 cells indicating quinone formation and intracellular GSH depletion played important mechanistic roles in ASA-induced melanoma toxicity. Ascorbic acid, a quinone reducing agent, and GSH, an antioxidant and quinone trap substrate, prevented ASA cell toxicity. Trifluoperazine, inhibitor of permeability transition pore in mitochondria, prevented ASA toxicity. ASA led to significant intracellular GSH depletion in melanocytic SK-MEL-28 melanoma cells but not in amelanotic C32 melanoma cells. ASA also led to significant reactive oxygen species (ROS) formation in melanocytic SK-MEL-28 melanoma cells but not in amelanotic C32 melanoma cells. ROS formation was exacerbated by dicoumarol and 1-bromoheptane in SK-MEL-28. Our investigation suggests that quinone species, intracellular GSH depletion, ROS formation, and mitochondrial toxicity significantly contributed toward ASA selective toxicity in melanocytic SK-MEL-28 melanoma cells.
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PMID:Biochemical mechanism of acetylsalicylic acid (Aspirin) selective toxicity toward melanoma cell lines. 1897 89

In this study, we demonstrated that transient transfection and over-expression of human mutant A53T alpha-synuclein (alpha-syn) could induce expression level- and time-dependent, non-apoptotic cell death in PC12 cells, while wild-type and mutant A30P alpha-syn could not. The non-apoptotic cell death induced by over-expression of A53T alpha-syn in PC12 cells was found to be dopamine (DA) related. It could be alleviated by nerve growth factor but not by chemicals that abrogate endoplasmic reticulum stress. Furthermore, PC12 cell death could be alleviated by N-acetyl-cysteine (NAC) as well as by L-cysteine; but not by cell permeable tyrosinase inhibitors. NAC could prevent DA auto-oxidation and tyrosinase-catalyzed DA oxidation, whereas L-cysteine could potently abrogate DA auto-oxidation but could not prevent tyrosinase-catalyzed DA oxidation. Both NAC and L-cysteine could increase the reduced and total GSH levels, and concurrently decrease the oxidized GSH level in PC12 cells. On the other hand, over-expression of human mutant A53T alpha-syn could decrease the reduced and total GSH levels, and increase the oxidized GSH level in the cells. Taken together, we concluded that auto-oxidation of endogenous DA aggravates non-apoptotic cell death induced by over-expression of human mutant A53T alpha-syn in PC12 cells.
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PMID:Dopamine auto-oxidation aggravates non-apoptotic cell death induced by over-expression of human A53T mutant alpha-synuclein in dopaminergic PC12 cells. 1904 8

Ultraviolet A (UVA) irradiation is suggested to contribute to melanogenesis through promoting cellular oxidative stress and impairing antioxidant defenses. An overproduction of melanin can be associated with melanoma skin cancer and hyperpigmentation. Therefore, developing effective antimelanogenic agents is of importance. Alpinia galanga (AG) and Curcuma aromatica (CA) are traditional medicinal plants widely used for skin problems. Hence, this study investigated the antimelanogenic effects of AG and CA extracts (3.8-30 microg/ml) by assessing tyrosinase activity, tyrosinase mRNA levels, and melanin content in human melanoma cells (G361) exposed to UVA. The roles in protecting against melanogenesis were examined by evaluating their inhibitory effects on UVA-induced cellular oxidative stress and modulation of antioxidant defenses including antioxidant enzymes, catalase (CAT) and glutathione peroxidase (GPx), and intracellular glutathione (GSH). In addition, possible active compounds accountable for biological activities of the extracts were identified by thin layer chromatography (TLC)-densitometric analysis. Our study demonstrated that UVA (8 J/cm(2)) induced both tyrosinase activity and mRNA levels and UVA (16 J/cm(2))-mediated melanin production were suppressed by the AG or CA extracts at noncytotoxic concentrations. Both extracts were able to protect against UVA-induced cellular oxidant formation and depletion of CAT and GPx activities and GSH content in a dose-dependent manner. Moreover, TLC-densitometric analysis detected the presence of eugenol and curcuminoids in AG and CA, respectively. This is the first report representing promising findings on AG and CA extract-derived antityrosinase properties correlated with their antioxidant potential. Inhibiting cellular oxidative stress and improving antioxidant defenses might be the mechanisms by which the extracts yield the protective effects on UVA-dependent melanogenesis.
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PMID:Modulation of antioxidant defense by Alpinia galanga and Curcuma aromatica extracts correlates with their inhibition of UVA-induced melanogenesis. 1928 16

Previously, we reported that acetaminophen (APAP) showed selective toxicity towards melanoma cell lines. In the current study, we investigated further the role of tyrosinase in APAP toxicity in SK-MEL-28 melanoma cells in the presence of a short hairpin RNA (shRNA) plasmid, silencing tyrosinase gene. Results from tyrosinase shRNA experiments showed that APAP led to negligible toxicity in shRNA plasmid-treated cells. It was also found that APAP selectively caused escalation in reactive oxygen species (ROS) formation and intracellular GSH (ICG) depletion in melanocytic human SK-MEL-28 and murine B16-F0 melanoma cells that express functional tyrosinase whereas it lacked significant effects on ROS formation and ICG in amelanotic C32 melanoma cells that do not express functional tyrosinase. These findings suggest that tyrosinase plays a major role in APAP selective induced toxicity in melanocytic melanoma cell lines. Furthermore, the in vivo efficacy and toxicity of APAP in the skin melanoma tumor model in mice was investigated. Mice receiving APAP at 60, 80, 100 and 300 mg/kg/day, day 7 through 13 post melanoma cell inoculation demonstrated tumor size growth inhibition by 7+/-14, 30+/-17, 45+/-11 and 57+/-3%, respectively. Mice receiving APAP day 1 through 13 post melanoma cell inoculation showed tumor size growth inhibition by 11+/-7, 33+/-9, 36+/-20 and 44+/-28%, respectively.
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PMID:Efficacy of acetaminophen in skin B16-F0 melanoma tumor-bearing C57BL/6 mice. 1951 68

In the present study, the ability of green tea catechins to induce electrophile-responsive element (EpRE)-mediated gene expression and the role of their quinones in the mechanism of this induction were investigated. To this end, Hepa1c1c7 mouse hepatoma cells were used, stably transfected with a luciferase reporter gene under the expression regulation of an EpRE from the human NAD(P)H:quinone oxidoreductase 1 (NQO1) gene. The results obtained show that several, but not all, catechins tested are able to induce EpRE-mediated gene transcription, with epigallocatechin gallate (EGCG) and gallocatechin gallate (GCG), both containing a pyrogallol and a galloyl moiety, being the most powerful inducers. Moreover, it was demonstrated that the EpRE-mediated response to catechins was increased in cells with reduced cellular glutathione (GSH) levels and decreased in cells with increased levels of GSH, corroborating a role for catechin quinones. The intrinsic capacity of catechins to form quinone type metabolites upon their oxidation was demonstrated using incubations of epigallocatechin (EGC) and EGCG with tyrosinase and the GSH-trapping method. Glutathione conjugates formed in these incubations were identified as 2'-glutathionyl-EGC, 2',6'-diglutathionyl-EGC, 2'-glutathionyl-EGCG, and 2',6'-diglutathionyl-EGCG, supporting the formation of quinone type metabolites involving especially the pyrogallol moiety of these catechins. Formation of the EGCG-quinone-glutathionyl adducts was also observed in the EpRE-LUX cellular system. This further supports the importance of the pyrogallol moiety for the quinone chemistry of the catechins. Finally, the presence of the pyrogallol moiety in the catechins also results in a relatively lower half-wave oxidation potential (E1/2) and calculated heat of formation (DHF) for conversion of the catechins to their corresponding quinones, pointing at an increased ability to become oxidized. Altogether, our studies reveal that catechins, especially those containing a pyrogallol moiety, induce EpRE-mediated detoxifying gene expression and that this induction is likely to be the result of their quinone chemistry.
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PMID:Role of catechin quinones in the induction of EpRE-mediated gene expression. 1954 56

Proanthocyanidins (PAs) are polymer chains of flavonoids known to have a high free radical scavenging capacity. However, their efficacy for use in dermatological health has not been fully explored. In the present study, we investigated the inhibitory property of PAs on melanogenesis and oxidative stress of cultured B16F10 melanoma cells (B16 cells) utilizing both oligomer and polymer PAs that were isolated from freshly crushed persimmon peel. To assess the suppressive effects of PAs against oxidative insults, lipid peroxidation, total reactive species (RS), peroxynitrite (ONOO(-)), superoxide ( O(2)), and nitric oxide (NO ) were quantitated. In addition, the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio was measured to evaluate the cellular oxidative status. Results showed that the PAs studied had a strong inhibitory effect on the murine tyrosinase and melanin synthesis that was correlated with the modulation of oxidative stress. Thus, our present work produced evidence that in B16 cells, the anti-melanogenic capacity of PAs as shown by the inhibition of tyrosinase and melanin synthesis likely occurs through the suppression of oxidative stress by the ability of PAs to modulate total RS, O(2), NO , ONOO(-), lipid peroxidation, and redox balance.
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PMID:Modulation of oxidative stress and melanogenesis by proanthocyanidins. 1957 77

We report the synthesis and preliminary in vitro biological evaluations of 4-[(4-hydroxyphenyl)sulfanyl]but-3-en-2-one, a compound designed as a potential bifunctional antimelanoma agent, bearing both a tyrosinase-activatable phenolic moiety and a GSH-reactive alpha,beta-unsaturated carbonyl group. Both the E (1) and Z (2) isomers of the synthesized compound proved to be very good substrates of mushroom tyrosinase, reacted quickly with GSH at physiological pH, and showed a significant cytotoxic activity against B16F1 murine melanoma cells.
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PMID:Synthesis and preliminary in vitro biological evaluation of 4-[(4-hydroxyphenyl)sulfanyl]but-3-en-2-one, a 4-mercaptophenol derivative designed as a novel bifunctional antimelanoma agent. 1960 48


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