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)

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

The effect of organo-sulfur compounds, including 1-propylmercaptan (PM), dimethyl disulfide (DMDS), diallyl disulfide (DADS), propyl disulfide (PDS), and 2,5-dimethylthiophene (DMT), on melanin formation was investigated. Among the selected five organo-sulfur compounds, PM displayed a significant inhibitory effect on tyrosinase activity (IC(50) = 0.5 mM) and the highest inhibitory action on o-quinone formation. In the B16 intracellular model system, the inhibitory action of selected five organo-sulfur compounds on tyrosinase activity and melanin formation may be, in part, attributed to the reduction of the reactive oxygen species (ROS) formation and positive modulation of the GSH/GSSG ratio in B16 cells. Among the five organo-sulfur compounds, PM appeared to be the most potent inhibitor of melanin formation. The analysis of inhibitory kinetics revealed that PM is a mixed-type inhibitor. This is the first study indicating that organo-sulfur compounds tested may play an important role in the regulation of melanin formation, making them the potent candidates for skin-whitening agents.
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PMID:Effects of selected organo-sulfur compounds on melanin formation. 1961 May 93

Sulfur-containing compounds heated under alkaline condition (pH 10) were determined for inhibitory activity toward polyphenol oxidase (PPO) from Pacific white shrimp (Litopenaeus vannamei) and for antioxidative activity. Cysteine and glutathione (GSH) (20 mM) heated at 100 degrees C at pH 10 strongly inhibited PPO activity. Heated alkaline cysteine showed the greater 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging activity, copper-chelating activity and reducing power than cysteine and glucose-cysteine Maillard reaction products (P < 0.05). Effect of heated alkaline cysteine at different concentrations (0, 20, and 100 mM) on the quality changes of Pacific white shrimp during iced storage was investigated. Shrimp treated with 100 mM heated alkaline cysteine had the lowest melanosis score, thiobarbituric acid-reactive substances (TBARS) value and total viable count (TVC), compared with those without treatment and treated with 20 mM heated alkaline cysteine, throughout the storage of 12 d (P < 0.05). Therefore, heated alkaline cysteine can be used as a novel additive to retard melanosis and extend the quality of postmortem shrimp.
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PMID:Sulfur-containing compounds heated under alkaline condition: antibrowning, antioxidative activities, and their effect on quality of shrimp during iced storage. 1972 29

The aim of this study was to identify a phenolic prodrug compound that is minimally metabolized by rat liver microsomes, but yet could form quinone reactive intermediates in melanoma cells as a result of its bioactivation by tyrosinase. In current work, we investigated 24 phenolic compounds for their metabolism by tyrosinase, rat liver microsomes and their toxicity towards murine B16-F0 and human SK-MEL-28 melanoma cells. A linear correlation was found between toxicities of phenolic analogs towards SK-MEL-28 and B16-F0 melanoma cells, suggesting similar mechanisms of toxicity in both cell lines. 4-HEB was identified as the lead compound. 4-HEB (IC(50) 48h, 75muM) showed selective toxicity towards five melanocytic melanoma cell lines SK-MEL-28, SK-MEL-5, MeWo, B16-F0 and B16-F10, which express functional tyrosinase, compared to four non-melanoma cells lines SW-620, Saos-2, PC3 and BJ cells and two amelanotic SK-MEL-24, C32 cells, which do not express functional tyrosinase. 4-HEB caused significant intracellular GSH depletion, ROS formation, and showed significantly less toxicity to tyrosinase specific shRNA transfected SK-MEL-28 cells. Our findings suggest that presence of a phenolic group in 4-HEB is critical for its selective toxicity towards melanoma cells.
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PMID:Structure-toxicity relationship of phenolic analogs as anti-melanoma agents: an enzyme directed prodrug approach. 1994 85

Phenoxyl radicals are inevitable intermediates in the oxidative enzymatic metabolism of a phenolic antitumour drug, etoposide (VP-16), by peroxidases, cytochrome P-450, prostaglandin synthetase and tyrosinase, as well as in its interactions with oxygen and peroxyl radicals. It has been shown that one-electron reduction of the VP-16 phenoxyl radical by ascorbate and thiols prevents/delays its oxidative metabolism by tyrosinase both in model systems and in cell homogenates. To elucidate the role of endogenous thiols in the reduction of VP-16 phenoxyl radicals, K562 human leukaemia cells grown in Dulbecco's modified Eagle's medium which does not contain vitamin C (ascorbate) were used, thus excluding the ascorbate-dependent reduction of VP-16 phenoxyl radicals. VP-16 phenoxyl radicals were reduced by endogenous reductants in K562 cell homogenates, intracellular thiols mainly being responsible. Depletion of endogenous thiols by mersalyl acid resulted in almost complete inhibition of the ability of cell homogenates to reduce VP-16 phenoxyl radicals. Three systems were used to evaluate the contribution of thiol-dependent reduction of VP-16 phenoxyl radicals: (1) K562 cell homogenates depleted or supplemented with glutathione (GSH) in vitro; (2) homogenates derived from K562 cells with a decreased level of endogenous thiols and GSH (using a specific inhibitor of gamma-glutamyl cysteine synthetase, buthionine-S,R-sulfoximine; BSO) and (3) homogenates derived from K562 cells with increased content of endogenous thiols as a result of treatment with cadmium chloride. Depletion of thiols in K562 cells or cell homogenates proportionally decreased the ability of homogenates to reduce VP-16 phenoxyl radicals. Similarly, depletion or supplementation of K562 cells or cell homogenates with GSH proportionally decreased or increased the ability to reduce VP-16 phenoxyl radicals. Reduction of VP-16 phenoxyl radicals by K562 cell homogenates was similar to that obtained from cell homogenates isolated from K/VP.5 cells, a VP-16 resistant cell line derived from K562 cells. Elevation of endogenous thiols by cadmium chloride increased the ability of homogenates to reduce VP-16 phenoxyl radicals but did not reveal any significant difference in the ability of the two types of cells to interact with VP-16 radicals. Finally, BSO treatment of K562 cells led to potentiation of VP-16-induced DNA damage and to an increase in VP-16-induced growth inhibition, suggesting that, in the absence of ascorbate, modulation of endogenous thiols may be an important factor determining the oxidative metabolism and cytotoxic activity of VP-16 in tumour cells.
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PMID:Reduction of phenoxyl radicals of the antitumour agent etoposide (VP-16) by glutathione and protein sulfhydryls in human leukaemia cells: Implications for cytotoxicity. 2065 Jan 83

In the current work, we investigated the in vitro biochemical mechanism of Caffeic Acid Phenylethyl Ester (CAPE) toxicity and eight hydroxycinnamic/caffeic acid derivatives in vitro, using tyrosinase enzyme as a molecular target in human SK-MEL-28 melanoma cells. Enzymatic reaction models using tyrosinase/O(2) and HRP/H(2)O(2) were used to delineate the role of one- and two-electron oxidation. Ascorbic acid (AA), NADH and GSH depletion were used as markers of quinone formation and oxidative stress in CAPE induced toxicity in melanoma cells. Ethylenediamine, an o-quinone trap, prevented the formation of o-quinone and oxidations of AA and NADH mediated by tyrosinase bioactivation of CAPE. The IC(50) of CAPE towards SK-MEL-28 melanoma cells was 15muM. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, increased CAPE's toxicity towards SK-MEL-28 cells indicating quinone formation played an important role in CAPE induced cell toxicity. Cyclosporin-A and trifluoperazine, inhibitors of the mitochondrial membrane permeability transition pore (PTP), prevented CAPE toxicity towards melanoma cells. We further investigated the role of tyrosinase in CAPE toxicity in the presence of a shRNA plasmid, targeting tyrosinase mRNA. Results from tyrosinase shRNA experiments showed that CAPE led to negligible anti-proliferative effect, apoptotic cell death and ROS formation in shRNA plasmid treated cells. Furthermore, it was also found that CAPE selectively caused escalation in the ROS formation and intracellular GSH (ICG) depletion in melanocytic human SK-MEL-28 cells which express functional tyrosinase. In contrast, CAPE did not lead to ROS formation and ICG depletion in amelanotic C32 melanoma cells, which do not express functional tyrosinase. These findings suggest that tyrosinase plays a major role in CAPE's selective toxicity towards melanocytic melanoma cell lines. Our findings suggest that the mechanisms of CAPE toxicity in SK-MEL-28 melanoma cells mediated by tyrosinase bioactivation of CAPE included quinone formation, ROS formation, intracellular GSH depletion and induced mitochondrial toxicity.
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PMID:Biochemical mechanism of caffeic acid phenylethyl ester (CAPE) selective toxicity towards melanoma cell lines. 2068 55


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