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)

The antimelanogenic activity of six hydrocoumarins and alpha-tocopherol (alpha-Toc) in normal human melanocytes was evaluated in both cell culture systems and cell homogenates. The inhibitory effects of hydrocoumarins depended upon their substituent groups. alpha-Toc and some of the hydrocoumarins inhibited melanogenesis in cultured normal human melanocytes, although they did not influence melanin synthesis in enzyme solution prepared as cell homogenates. In addition, alpha-Toc and the hydrocoumarins stimulated intracellular glutathione (GSH) synthesis. In particular, 7-allyl-6-hydroxy-4,4,5,8-tetramethylhydrocoumarin strongly inhibited melanogenesis and intracellular GSH synthesis in normal human melanocytes, more so than alpha-Toc. Furthermore, hydrocoumarins exhibited higher scavenging and quenching activities against with tert-butyl peroxyl radicals and singlet oxygen species. These results suggest that 7-allyl-6-hydroxy-4,4,5,8-tetramethyl hydrocoumarin would be useful as an antimelanogenic agent for the prevention or improvement of skin pigmentation induced by reactive oxygen compounds and free radicals, and may inhibit melanogenesis, including tyrosinase transfer and melanosome differentiation, by interrupting melanization by increasing the intracellular GSH content.
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PMID:Antimelanogenic activity of hydrocoumarins in cultured normal human melanocytes by stimulating intracellular glutathione synthesis. 1242 Jan 3

A tyrosinase-directed therapeutic approach for malignant melanoma therapy uses the depigmenting phenolic agents such as 4-hydroxyanisole (4-HA) to form cytotoxic o-quinones. However, renal and hepatic toxicity was reported as side effects in a recent 4-HA clinical trial. In search of novel therapeutics, the cytotoxicity of the isomers 4-HA, 3-HA and 2-HA were investigated. In the following, the order of the HAs induced hepatotoxicity in mice, as measured by increased in vivo plasma transaminase activity, or in isolated rat hepatocytes, as measured by trypan blue exclusion, was 3-HA > 2-HA > 4-HA. Hepatocyte GSH depletion preceded HA induced cytotoxicity and a 4-MC-SG conjugate was identified by LC/MS/MS mass spectrometry analysis when 3-HA was incubated with NADPH/microsomes/GSH. 3-HA induced hepatocyte GSH depletion or GSH depletion when 3-HA was incubated with NADPH/microsomes was prevented by CYP 2E1 inhibitors. Dicumarol (an NAD(P)H: quinone oxidoreductase inhibitor) potentiated 3-HA- or 4-methoxycatechol (4-MC) induced toxicity whereas sorbitol (an NADH generating nutrient) greatly prevented cytotoxicity indicating a quinone-mediated cytotoxic mechanism. Ethylendiamine (an o-quinone trap) largely prevented 3-HA and 4-MC-induced cytotoxicity indicating that o-quinone was involved in cytotoxicity. Dithiothreitol (DTT) greatly reduced 3-HA and 4-MC induced toxicity. The ferric chelator deferoxamine slightly decreased 3-HA and 4-MC induced cytotoxicity whereas the antioxidants pyrogallol or TEMPOL greatly prevented the toxicity suggesting that oxidative stress contributed to 3-HA induced cytotoxicity. In summary, ring hydroxylation but not O-demethylation/epoxidation seems to be the bioactivation pathway for 3-HA in rat liver. The cytotoxic mechanism for 3-HA and its metabolite 4-MC likely consists cellular protein alkylation and oxidative stress. These results suggest that 3-HA is not suitable for treatment of melanoma.
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PMID:Metabolic activation of 3-hydroxyanisole by isolated rat hepatocytes. 1245 69

The human copper chaperone HAH1 transports copper to the Menkes and Wilson proteins, which are copper-translocating P-type ATPases located in the trans-Golgi apparatus and believed to provide copper for important enzymes such as ceruloplasmin, tyrosinase, and peptidylglycine monooxygenase. Although a substantial amount of structural data exist for HAH1 and its yeast and bacterial homologues, details of the copper coordination remain unclear and suggest the presence of two protein-derived cysteine ligands and a third exogenous thiol ligand. Here we report the preparation and reconstitution of HAH1 with Cu(I) using a protocol that minimizes the use of thiol reagents believed to be the source of the third ligand. We show by x-ray absorption spectroscopy that this reconstitution protocol generates an occupied Cu(I) binding site with linear biscysteinate coordination geometry, as evidenced by (i) an intense edge absorption centered at 8982.5 eV, with energy and intensity identical to the rigorously linear two-coordinate model complex bis-2,3,5,6-tetramethylbenzene thiolate Cu(I) and (ii) an EXAFS spectrum that could be fit to two Cu-S interactions at 2.16 A, a distance typical of digonal Cu(I) coordination. Binding of exogenous ligands (GSH, dithiothreitol, and tris-(2-carboxyethyl)-phosphine) to the Cu(I) was investigated. When GSH or dithiothreitol was added to the chaperone during the reconstitution procedure, the resulting Cu(I)- HAH1 remained two-coordinate, whereas the addition of the phosphine during reconstitution elicited a three-coordinate species. When the exogenous ligands were titrated into the Cu(I)-HAH1, all formed three-coordinate adducts but with differing affinities. Thus, GSH and dithiothreitol showed weaker binding, with estimated KD values in the range 10-25 mm, whereas tris-(2-carboxyethyl)-phosphine showed stronger affinity, with a KD value of <5 mm. The implications of these findings for mechanisms of copper transport are discussed.
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PMID:X-ray absorption spectroscopy of the copper chaperone HAH1 reveals a linear two-coordinate Cu(I) center capable of adduct formation with exogenous thiols and phosphines. 1268 48

Estrogen replacement therapy has been correlated with an increased risk for developing breast and endometrial cancers. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols, which are further oxidized to electrophilic/redox active o-quinones that have the potential to both initiate and promote the carcinogenic process. Previously, we showed that the equine estrogens, equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are primarily metabolized to the catechol, 4-hydroxyequilenin. This catechol was found to autoxidize to an o-quinone causing oxidation and alkylation of DNA in vitro and in vivo. To block catechol formation from equilenin, 4-halogenated equilenin derivatives were synthesized. These derivatives were tested for their ability to bind to the estrogen receptor, induce estrogen sensitive genes, and their potential to form catechol metabolites. We found that the 4-fluoro derivatives were more estrogenic than the 4-chloro and 4-bromo derivatives as demonstrated by a higher binding affinity for estrogen receptors alpha and beta, an enhanced induction of alkaline phosphatase activity in Ishikawa cells, pS2 expression in S30 cells, and PR expression in Ishikawa cells. Incubation of these compounds with tyrosinase in the presence of GSH showed that the halogenated equilenin compounds formed less catechol GSH conjugates than the parent compounds, equilenin and 17beta-hydroxyequilenin. In addition, these halogenated compounds showed less cytotoxicity in the presence of tyrosinase than the parent compounds in S30 cells. Also, as stated above, the 4-fluoro derivatives showed similar estrogenic effects as compared with parent compounds; however, they were less toxic in S30 cells as compared to equilenin and 17beta-equilenin. Because 17beta-hydroxy-4-halogenated equilenin derivatives showed higher estrogenic effects than the halogenated equilenin derivatives in vitro, we studied the relative ability of the 17beta-hydroxy-4-halogenated equilenin derivatives to induce estrogenic effects in the ovariectomized rat model. The 4-fluoro derivative showed higher activity than 4-chloro and 4-bromo derivatives as demonstrated by inducing higher vaginal cellular differentiation, uterine growth, and mammary gland branching. However, 17beta-hydroxy-4-fluoroequilenin showed a lower estrogenic activity than 17beta-hydroxyequilenin and estradiol, which could be due to alternative pharmacokinetic properties for these compounds. These data suggest that the 4-fluoroequilenin derivatives have promise as alternatives to traditional estrogen replacement therapy due to their similar estrogenic properties with less overall toxicity.
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PMID:Effect of halogenated substituents on the metabolism and estrogenic effects of the equine estrogen, equilenin. 1280 57

Ifosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon-gamma (IFN-gamma) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-gamma. The decrease in allostimulatory capacity and in IFN-gamma and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function.
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PMID:Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion. 1285 64

Chlorogenic acid (1), a cancer chemopreventive agent widely found in fruits, tea and coffee, undergoes efficient conjugation with glutathione (GSH), in the presence of horseradish peroxidase/H(2)O(2) or tyrosinase at pH 7.4, to yield three main adducts that have been isolated and identified as 2-S-glutathionylchlorogenic acid (3), 2,5-di-S-glutathionylchlorogenic acid (4) and 2,5,6-tri-S-glutathionylchlorogenic acid (5) by extensive NMR analysis. The same pattern of products could be obtained by reaction of 1 with GSH in the presence of nitrite ions in acetate buffer at pH 4. Mechanistic experiments suggested that oxidative conjugation reactions proceed by sequential nucleophilic attack of GSH on ortho-quinone intermediates. Overall, these results provide the first complete spectral characterization of the adducts generated by biomimetic oxidation of 1 in the presence of GSH, and disclose a new possible nitrite-mediated conjugation pathway of 1 with GSH at acidic pH of physiological relevance.
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PMID:Oxidative conjugation of chlorogenic acid with glutathione. Structural characterization of addition products and a new nitrite-Promoted pathway. 1455 96

Melanogenesis provides a unique target for the development of antitumour agents specific for malignant melanoma. Among the anti-melanoma compounds we have examined, 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine, was found to have the most promising anti-melanoma effects. To further improve its efficacy as an anti-melanoma agent, we synthesized the R- and S-enantiomers (99% enantiomer excess) of alpha-methyl- 4-S-cysteaminylphenol (alpha-Me-4-S-CAP) and alpha-ethyl- 4-S-cysteaminylphenol (alpha-Et-4-S-CAP) by coupling 4-hydroxythiophenol with the oxazolines obtained from the (R)- and (S)-enantiomers of 2-amino-1-propanol and 2-amino-1-butanol, respectively. The enantiomers of alpha-Me-4-S-CAP and alpha-Et-4-S-CAP were found to be better substrates for tyrosinase than the natural substrate, L-tyrosine. In vitro experiments showed that all four enantiomers were highly cytotoxic to pigmented B16-F1 melanoma cells, the effect being 70-fold and 160-fold greater than that on non-pigmented B16-G4F melanoma cells and 3T3 fibroblasts, respectively. The cytotoxic effect against B16-F1 cells was completely inhibited by phenylthiourea, a tyrosinase inhibitor, or by N-acetyl-L-cysteine, which increases the intracellular reduced glutathione (GSH) level. 4-S-CAP and the enantiomers were taken up into B16-F1 cells at comparable rates, but showed varying rates of GSH depletion that were inversely correlated to the cytotoxicity. These results suggest that the use of enantiomers would increase the efficacy of tyrosinase-dependent cytotoxic phenols.
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PMID:Synthesis and selective in vitro anti-melanoma effect of enantiomeric alpha-methyl- and alpha-ethyl-4-S-cysteaminylphenol. 1464 24

Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a flavone with putative ability to prevent cancer and cardiovascular diseases. Its metabolism was evaluated in rats and human. Rats received quercetin via the intravenous (i.v.) route and metabolites were isolated from the plasma, urine and bile. Analysis was by high-performance liquid chromatography and confirmation of species identity was achieved by mass spectrometry. Quercetin and isorhamnetin, the 3'-O-methyl analogue, were found in both the plasma and urine. In addition, several polar peaks were characterised as sulphated and glucuronidated conjugates of quercetin and isorhamnetin. Extension of the metabolism studies to a cancer patient who had received quercetin as an i.v. bolus showed that (Quercetin removed) isorhamnetin and quercetin 3'-O-sulphate were major plasma metabolites. As a catechol, quercetin can potentially be converted to a quinone and subsequently conjugated with glutathione (GSH). Oxidation of quercetin with mushroom tyrosinase in the presence of GSH furnished GSH conjugates of quercetin, two mono- and one bis-substituted conjugates. However, these species were not found in biomatrices in rats treated with quercetin. As cyclo-oxygenase-2 (COX-2) expression is mechanistically linked to carcinogenesis, we examined whether quercetin and its metabolites can inhibit COX-2 in a human colorectal cancer cell line (HCA-7). Isorhamnetin and its 4'-isomer tamarixetin were potent inhibitors, reflected in a 90% decrease in prostaglandin E-2 (PGE-2) levels, a marker of COX-2 activity. Quercetin was less effective, with a 50% decline. Quercetin 3- and 7-O-sulphate had no effect on PGE-2. The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites.
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PMID:Characterisation of metabolites of the putative cancer chemopreventive agent quercetin and their effect on cyclo-oxygenase activity. 1529 28

Although approved for the treatment of hormone-dependent breast cancer as well as for the prevention of breast cancer in high-risk women, the selective estrogen receptor modulator (SERM) tamoxifen has been associated with an increased risk of endometrial cancer in women. With an understanding of the potential carcinogenic mechanisms of these compounds, SERMs could in principle be designed or selected for use that avoids these problems. Acolbifene (EM-652) is a fourth-generation SERM and the active form of the ester prodrug EM-800. As a pure antagonist of breast tumor development and growth, acolbifene does not stimulate endometrial tissue. However, acolbifene was found in this investigation to form two kinds of quinone methides, either through chemical or through enzymatic oxidation. One was a classical acolbifene quinone methide, which was formed by oxidation at the C-17 methyl group, and the other was a diquinone methide involving the oxidation of two phenol groups. The half-life of the classical quinone methide was determined to be 32 +/- 0.4 s at physiological pH and temperature. The quinone methides reacted with glutathione (GSH) to form five mono-GSH conjugates and five di-GSH conjugates. The majority of GSH conjugates resulted from reaction of the classical acolbifene quinone methide with GSH. Incubations of acolbifene with GSH and either tyrosinase or human and rat liver microsomes also produced acolbifene quinone methide-GSH conjugates. In addition to reaction with GSH, the classical acolbifene quinone methide was also shown to react with deoxynucleosides. One of the major deoxynucleoside adducts was identified as the deoxyadenosine adduct resulting from reaction of the classical acolbifene quinone methide with the exocyclic amino group of adenine. Acolbifene could also induce DNA damage in the S30 breast cancer cell line. These data imply that the classical electrophilic acolbifene quinone methide might contribute to the potential toxicity of acolbifene.
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PMID:Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. 1572 Jan 21

In our previous study, we showed that 4,4'-dihydroxybiphenyl (44'-BP) reduced melanin content via the inhibition of tyrosinase. In the current study, we utilized 44'-BP treated B16 melanoma cells (B16 cells) to measure several key cellular parameters known to be involved in melanogenic activity. Included in these measurements were tyrosinase and microphthalmia transcription factor (MITF) protein levels, cyclic AMP levels, protein kinase A (PKA) activation, and reduced glutathione (GSH) and oxidized glutathione (GSSG) levels. Results showed that 44'-BP effectively suppressed the amounts of tyrosinase and MITF proteins, cAMP levels, and PKA activation. In addition, 44'-BP enhanced the GSH/GSSG ratio. In conclusion, our data provide an evidence that 44'-BP suppressed several cellular key parameters in the melanogenic pathway by downregulating the cAMP-dependent PKA signaling pathway and decreasing MITF gene expression (implied from the reduced protein levels), which in turn suppressed tyrosinase. We propose that the antimelanogenic action of 44'-BP is likely carried out by a combined effect of its anti-oxidant property and its ability to enhance intracellular GSH levels.
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PMID:Inhibition of melanogenic activity by 4,4'-dihydroxybiphenyl in melanoma cells. 1639 1


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