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)

In the current work we investigated for the first time the biochemical basis of 4-hydroxyanisole (4-HA) induced toxicity in B16-F0 melanoma cells. It was found that dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, increased 4-HA induced toxicity towards B16-F0 cells whereas dithiothreitol, a thiol containing agent, and ascorbic acid (AA), a reducing agent, largely prevented 4-HA toxicity. TEMPOL and pyrogallol, free radical scavengers, did not significantly prevent 4-HA toxicity towards B16-F0 cells. GSH>AA>NADH prevented the o-quinone formation when 4-HA was metabolized by tyrosinase/O(2). 4-HA metabolism by horseradish peroxidase/H(2)O(2) was prevented more effectively by AA than NADH>GSH. We therefore concluded that quinone formation was the major pathway for 4-HA induced toxicity in B16-F0 melanoma cells whereas free radical formation played a negligible role in the 4-HA induced toxicity.
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PMID:Biochemical basis of 4-hydroxyanisole induced cell toxicity towards B16-F0 melanoma cells. 1642 88

To find novel skin-whitening agents, the melanogenesis inhibitory action of gallic acid (GA) was investigated. In this current study, the effects of GA on mushroom tyrosinase, tyrosinase inhibitory activity, and melanin content were assessed in B16 melanoma cells (B16 cells). Results indicated that GA has a strong antityrosinase activity (IC50=3.59x10(-6) M). Furthermore, data on murine tyrosinase activity and melanin biosynthesis revealed that GA effectively suppressed murine tyrosinase action and the amount of melanin. To investigate the relation between GA's inhibition of melanogenesis and antioxidant activity, the effect of GA on reactive species (RS) generation and the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in were determined in B16 cells. Results indicated that GA effectively down-regulated the RS generation and enhanced the GSH/GSSG ratio. Based on these results, I propose that GA exerts antimelanogenic activity coupled with antioxidant properties by suppressing RS generation and maintaining a higher GSH/GSSG ratio.
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PMID:Antimelanogenic and antioxidant properties of gallic acid. 1754 Nov 53

The metabolism and toxicity of ethyl 4-hydroxybenzoate (4-HEB) were investigated in vitro using tyrosinase enzyme, a melanoma molecular target, and CYP2E1 induced rat liver microsomes, and in human SK-MEL-28 melanoma cells. The results were compared to 4-hydroxyanisole (4-HA). At 90 min, 4-HEB was metabolized 48% by tyrosinase and 26% by liver microsomes while the extent of 4-HA metabolism was 196% and 88%, respectively. The IC50 (day 2) of 4-HEB and 4-HA towards SK-MEL-28 cells were 75 and 50 microM, respectively. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, increased 4-HEB toxicity towards SK-MEL-28 cells indicating o-quinone formation played an important role in 4-HEB induced cell toxicity. Addition of ascorbic acid and GSH to the media was effective in preventing 4-HEB cell toxicity. Cyclosporin A and trifluoperazine, inhibitors of permeability transition pore in mitochondria, were significantly potent in inhibiting 4-HEB cell toxicity. 4-HEB caused time-dependent decline in intracellular GSH concentration which preceded cell death. 4-HEB also led to reactive oxygen species (ROS) formation in melanoma cells which exacerbated by dicoumarol and 1-bromoheptane whereas cyclosporin A and trifluoperazine prevented it. Our findings suggest that the mechanisms of 4-HEB toxicity in SK-MEL-28 were o-quinone formation, intracellular GSH depletion, ROS formation and mitochondrial toxicity.
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PMID:Metabolic bioactivation and toxicity of ethyl 4-hydroxybenzoate in human SK-MEL-28 melanoma cells. 1784 68

The effect of paclobutrazol (PBZ) treatments on the antioxidant metabolism of white yam (Dioscorea rotundata Poir.) was investigated in the present study. PBZ @ 15 mg l(-1) plant(-1) was given to plants by soil drenching, 30, 60, and 90 days after planting (DAP). The non-enzymatic antioxidant contents like ascorbic acid (AA), reduced glutathione (GSH) and alpha-tocopherol (alpha-toc), activities of antioxidant enzymes like superoxide dismutase (SOD), ascorbate peroxidase (APX), polyphenol oxidase (PPO) and catalase (CAT) were extracted and assayed on 100 DAP from leaf, stem and tubers of both control and PBZ treated plants. It was found that PBZ has a profound effect on the antioxidant metabolism and caused an enhancement in both non-enzymatic and enzymatic antioxidant potentials under treatments in white yam. Our results have good significance, as this increase the innate antioxidant potential of this food crop, which is helpful to satisfy the needs of antioxidants in diet and thereby make it an economically important food crop.
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PMID:Responses of antioxidant potentials in Dioscorea rotundata Poir. following paclobutrazol drenching. 1792 73

Combretastatins are stilbene-based, tubulin depolymerization agents with selective activity against the tumor vasculature; two variants (A-1 and A-4) are currently undergoing clinical trials. Combretastatin A-1 (CA1) has a greater antitumor effect than combretastatin A-4 (CA4). We hypothesized that this reflects the enhanced reactivity conferred by the second (ortho) phenolic moiety in CA1. Oxidation of CA1 by peroxidase, tyrosinase, or Fe(III) generates a species with mass characteristics of the corresponding ortho-quinone Q1. After administration of CA1-bis(phosphate) to mice, the hydroquinone-thioether conjugate Q1H2-SG, formed from the nucleophilic addition of GSH to Q1, was detected in liver. In competition, electrocyclic ring closure of Q1, over a few minutes at pH 7.4, leads to a second ortho-quinone product Q2, characterized by exact mass and NMR. This product was also generated by human promyelocytic leukemia (HL-60) cells in vitro, provided that superoxide dismutase was added. Q2 is highly reactive toward glutathione (GSH) and ascorbate, stimulating oxygen consumption in a catalytic manner. Free radical intermediates formed during autoxidation of CA1 were characterized by EPR, and the effects of GSH and ascorbate on the signals were studied. Pulse radiolysis was used to initiate selective one-electron oxidation or reduction and provided further evidence, from the differing absorption spectra of the radicals formed on oxidation of CA1 or reduction of Q2, that two different quinones were formed on oxidation of CA1. The results demonstrate fundamental differences between the pharmacological properties of CA1 and CA4 that provide two possible explanations for their differential activities in vivo: oxidative activation to a quinone intermediate likely to bind to protein thiols and possibly to nucleic acids and stimulation of oxidative stress by enhancing superoxide/hydrogen peroxide production. The observation of the GSH conjugate Q1H2-SG in vivo provides a new marker for oxidative metabolism of relevance to current clinical trials of CA1-bis(phosphate) (OXi4503).
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PMID:Oxidative metabolism of combretastatin A-1 produces quinone intermediates with the potential to bind to nucleophiles and to enhance oxidative stress via free radicals. 1794 99

In our efforts to find new skin lightening agents, piceatannol (PICE) was investigated for its antioxidative property and ability to inhibit melanogenesis. In this study, PICE's effect on inhibition of mushroom tyrosinase, and tyrosinase inhibiting activity and melanin content were assessed utilizing the B16F10 melanoma cell (B16 cell) culture system. Results indicated that PICE has a strong antityrosinase activity (IC(50)=1.53 microM). To evaluate the relative efficacy of PICE compared to other tyrosinase inhibitors, its inhibitory effect was compared and showed that PICE was significantly stronger than kojic acid (IC(50)=50.1 microM) and resveratrol (IC(50)=63.2 microM). Furthermore, PICE was shown to down-regulate melanin content. To document PICE's antioxidative property, which is known to influence melanogenic activity, we assessed reactive species (RS) generation, reduced glutathione (GSH) and oxidized glutathione (GSSG) levels in these B16 cells. The results showed that PICE suppressed RS generation and enhanced the GSH/GSSG ratio. In conclusion, our results indicated that the antimelanogenic action of PICE is likely exhibited by the combined effect of PICE's antioxidative property and its ability to suppress RS generation while increasing the GSH/GSSG ratio.
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PMID:Piceatannol inhibits melanogenesis by its antioxidative actions. 1797 67

Tyrosinase is expressed in melanoma cells and catalyzes the formation of 3,3',4',5,7-pentahydroxyflavone (quercetin) into reactive quinone species and subsequent glutathionyl adducts. Therefore, we examined the effect of quercetin metabolism on the glutathione (GSH) bioreduction pathway and cell viability in DB-1 melanoma cells that express varying levels of tyrosinase (Tyr+). In a cell-free system, GSH was significantly decreased by quercetin, which coincided with the formation of glutathionyl adducts. In Tyr+ clones, quercetin decreased bioreduction capacity and increased reactive oxygen species (ROS) to a greater degree compared to control cells. The antioxidant/electrophile response element-induced enzymes, glutathione-S-transferase (GST), and nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 were expressed at high levels in Tyr+ cells and contributed to pro-oxidant quercetin metabolism. The basal level of ROS and apoptosis was higher in Tyr+ cells and were selectively increased after exposure to quercetin. The increase in apoptosis following quercetin exposure was p53/Bax mediated and correlated with a decrease in GST-driven bioreduction capacity and an increase in ROS. In conclusion, quercetin can selectively sensitize Tyr+ expressing melanoma cells to apoptosis and may serve as an adjuvant to chemotherapy by enhancing cell death and interfering with GST-mediated drug resistance.
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PMID:Quercetin selectively inhibits bioreduction and enhances apoptosis in melanoma cells that overexpress tyrosinase. 1800 Dec 20

The variations in antioxidant potentials and indole alkaloid content were studied in the present investigation, in two varieties (rosea and alba) of Catharanthus roseus, an important herb used in traditional as well as modern medicine, exposed to water deficit stress. The antioxidant and alkaloid profiles were estimated from root, stem, leaf, flowers and pods. The antioxidant potentials were examined in terms of non-enzymatic antioxidant molecules and activities of antioxidant enzymes. The non-enzymatic antioxidant molecules studied were ascorbic acid (AA), alpha-tocopherol (alpha-toc) and reduced glutathione (GSH). The estimated antioxidant enzymes were superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), peroxidase (POX) and polyphenol oxidase (PPO). The antioxidant concentrations and activities of antioxidant enzymes were high under water deficit stress in all parts of the plants. Indole alkaloid content was high in the roots of rosea variety in response to stress when compared to alba variety.
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PMID:Antioxidant potential and indole alkaloid profile variations with water deficits along different parts of two varieties of Catharanthus roseus. 1806 39

PH-302 ( 1) demonstrates potent inhibitory activity against the inducible form of nitric oxide synthase (iNOS). The primary metabolite of PH-302 is a catechol ( 2) resulting from oxidative demethylenation of the methylenedioxyphenyl moiety by cytochrome P450 3A4. Concerns regarding subsequent two-electron oxidation of 2 to an electrophilic quinone species and the potential for resulting toxicity prompted additional studies to examine the reactivity and metabolic fate of this metabolite. Contrary to literature reports of catechol reactivity, 2 appeared to be resistant to quinone formation in human liver microsomal incubations, as determined by the lack of detectable glutathione (GSH) adducts and no covalent binding to microsomal proteins. In addition, 2 showed no evidence of depletion of intracellular glutathione or cytotoxicity at concentrations up to 1 mM in primary human and rat hepatocytes. In the presence of tyrosinase, spectral evidence indicated that 2 was oxidized to the ortho-quinone, and upon incubation in the presence of GSH, two conjugates were detected and characterized by LC/MS/MS. Lastly, the metabolic pathways of 2 were investigated in rat and human hepatocytes and found to be similar, proceeding via glucuronidation, sulfation, and methylation of the catechol. Collectively, these studies demonstrate that 2 appears to be resistant to further oxidation to quinone in liver microsomes, as well as spontaneous redox cycling, while the formation of phase II metabolites in hepatocytes suggests that multiple detoxication pathways may provide added protection against toxicity in the liver.
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PMID:Assessment of the metabolism and intrinsic reactivity of a novel catechol metabolite. 1840 75

The significance of plant growth-promoting rhizobacteria (PGPR) mediated increase in antioxidant potential in vegetables is yet unknown. The plant growth-promoting bacterium Bacillus lentimorbus NRRL B-30488 (B-30488) mediated induction of dietary antioxidant in vegetables ( Trigonella foenum-graecum, Lactuca sativa, Spinacia oleracea, and Daucus carota) and fruit ( Citrus sinensis) after minimal processing (fresh, boiled, and frozen) was tested by estimating the total phenol content, level of antioxidant enzymes, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) and superoxide scavenging activities along with integral radical scavenging capacity by photochemiluminescence assay and inhibition of lipid peroxidation. Minimal processing of vegetables showed that T. foenum-graecum had the highest phenol content in B-30488-treated plants followed by L. sativa, D. carota, and S. oleracea. Thermally treated vegetables T. foenum-graecum (26-114.5 GAE microg mg (-1)) had an exceptionally high total phenolic content, followed by D. carota (25.27-101.32 GAE microg mg (-1)), L. sativa (23.22-101.10 GAE microg mg (-1)), and S. oleracea (21.87-87.57 GAE microg mg (-1)). Among the vegetables and fruit used in this study for enzymatic estimation, induction of antioxidant enzymes, namely, polyphenol oxidase (PPO), ascorbate peroxidase (APX), catalase (CAT), and superoxidase dismutase (SOD), was observed in edible parts of T. foenum-graecum, L. sativa, S. oleracea, and D. carota, after inoculation with B-30488. The scavenging capacity of the vegetables treated with B-30488 against DPPH and superoxide anion radical activity was found to be significantly high as compared to nontreated control. Mild food processing had no adverse effect on radical scavenging capacity. Photochemiluminescence also ascertains the above findings. The ability of the plant extracts to protect against lipid peroxidation and its ability to prevent oxidation of reduced glutathione (GSH) was measured in rat liver homogenate, and the results suggested that the inoculated plant exhibited better activity in all of the screened plants. Significant increases in shoot length, root length, and dry weight, averaging 164, 132, and 135% in T. foenum-graecum, 174, 141, and 156% in L. sativa, 129, 141, and 59%, in S. oleracea, and 125, 146, and 42% in D. carota, respectively, over untreated controls, were attained in greenhouse trials. To the best of the authors' knowledge, this is the first report of PGPR-mediated induction of antioxidant enzyme activity (PPO, APX, CAT, and SOD) along with the antioxidant activity of the extracts in both in vitro (DPPH radical scavenging and superoxide scavenging) and ex vivo conditions using the rat liver tissue (percent inhibition of lipid peroxidation and prevention of oxidation of GSH) and phenolic content. The results demonstrate the PGPR-mediated induction of antioxidant level in vegetables and fruit controls oxidative damage even after minimal processing and thus is indicative of its potential as a viable substitute of synthetic antioxidants.
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PMID:Novel mechanism of modulating natural antioxidants in functional foods: involvement of plant growth promoting Rhizobacteria NRRL B-30488. 1849 12


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