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Food and Chemical Toxicology : An... Nov 2017Various chemical compounds can inflict developmental toxicity when sufficiently high concentrations are exposed to embryos at the critical stages of development....
Various chemical compounds can inflict developmental toxicity when sufficiently high concentrations are exposed to embryos at the critical stages of development. Excipients, such as coloring agents and preservatives, are pharmacologically inactive ingredients that are included in various medications, foods, and cosmetics. However, concentrations that may adversely affect embryo development are largely unknown for most excipients. Here, the lowest observed adverse effect level (LOAEL) to inflict developmental toxicity was assessed for three coloring agents (allura red, brilliant blue, and tartrazine) and three preservatives (butylated hydroxyanisole, metabisulfite, and methylparaben). Adverse impact of a compound exposure was determined using the stem cell-based in vitro morphogenesis model, in which three-dimensional cell aggregates, or embryoid bodies (EBs), recapitulate embryonic processes of body axis elongation and patterning. LOAEL to impair EB morphogenesis was 200 μM for methylparaben, 400 μM for butylated hydroxyanisole, 600 μM for allura red and brilliant blue, and 1000 μM for metabisulfite. Gene expression analyses of excipient-treated EBs revealed that butylated hydroxyanisole and methylparaben significantly altered profiles of developmental regulators involved in axial elongation and patterning of the body. The present study may provide a novel in vitro approach to investigate potential developmental toxicity of common excipients with mechanistic insights.
Topics: Animals; Cell Line; Cell Proliferation; Coloring Agents; Embryonic Development; Embryonic Stem Cells; Excipients; Gene Expression Regulation, Developmental; Mice; Preservatives, Pharmaceutical
PubMed: 28927898
DOI: 10.1016/j.fct.2017.09.023 -
The Journal of Biological Chemistry Mar 1989The food antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are shown to be metabolized to covalent binding intermediates and various other...
The peroxidase-dependent activation of butylated hydroxyanisole and butylated hydroxytoluene (BHT) to reactive intermediates. Formation of BHT-quinone methide via a chemical-chemical interaction.
The food antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are shown to be metabolized to covalent binding intermediates and various other metabolites by prostaglandin H synthase and horseradish peroxidase. BHA was extensively metabolized by horseradish peroxidase (80% conversion of parent BHA into metabolites) resulting in the formation of three dimeric products. Only two of these dimers were observed in prostaglandin H synthase-catalyzed reactions. In contrast to BHA, BHT proved to be a relatively poor substrate for prostaglandin synthase and horseradish peroxidase, resulting in the formation of a small amount of polar and aqueous metabolites (23% conversion of parent BHT into metabolites). With arachidonic acid as the substrate, prostaglandin H synthase catalyzed the covalent binding of [14C]BHA and [14C]BHT to microsomal protein which was significantly inhibited by indomethacin and glutathione. The covalent binding of BHA and its metabolism to dimeric products were also inhibited by BHT. In contrast, the addition of BHA enhanced the covalent binding of BHT by 400%. Moreover, in the presence of BHA, the formation of the polar and aqueous metabolites of BHT was increased and two additional metabolites, BHT-quinone methide and stilbenequinone, were detected. The increased peroxidase-dependent oxidation of BHT in the presence of BHA is proposed to occur via the direct chemical interaction of BHA phenoxyl radical with BHT or BHT phenoxyl radical. These results suggest a potential role for phenoxyl radicals in the activation of xenobiotic chemicals to toxic metabolites.
Topics: Butylated Hydroxyanisole; Butylated Hydroxytoluene; Glutathione; Horseradish Peroxidase; In Vitro Techniques; Lactoperoxidase; Oxidation-Reduction; Peroxidases; Prostaglandin-Endoperoxide Synthases; Proteins; Quinones; Spectrophotometry; Xenobiotics
PubMed: 2492993
DOI: No ID Found -
Toxicology Reports 2018Carbon tetrachloride (CCl), a hepatotoxic agent is widely used to study the toxic mechanisms in experimental animals. This study was carried out to establish the...
Carbon tetrachloride (CCl), a hepatotoxic agent is widely used to study the toxic mechanisms in experimental animals. This study was carried out to establish the hepatoprotective measures of food preservative antioxidants butylated hydroxyanisole and butylated hydroxytolune (BHA, BHT) when mixed with food towards carbon tetrachloride (CCl) intoxication (230 mg/ kg b wt/rat/day) in rat. Biochemical markers like serum glutamate pyruvate tranaminase (AST), serum glutamate oxaloacetate transaminase (ALT), alkaline phosphatase (ALP) and bilirubin content, antioxidant enzymes such as SOD, CAT, GPx, and malondialdehyde (MDA) as the end product of lipid peroxidanion were measured. The results had shown the elevated level of AST (121.16%), ALT (124.68%), ALP (122.41%) an, bilirubin content (57.14%) after CCl treatment. Marked decrease of activity of antioxidant enzymes such as SOD (85.36%), CAT (67.47%), GPx (50.7%) had indicated that the ROS mediated toxicity and pretreatment of BHA and BHT restored the activity of these enzymes. High level of MDA content with reduced GSH value was also observed due to oxidative stress. The hepatic antioxidant status was restored with the food preservative (BHA, BHT) antioxidant treatment which had indicated the significant protective effect against CCl induced hepatotoxicity and finally confirmed by histopathological studies.
PubMed: 29276688
DOI: 10.1016/j.toxrep.2017.12.009 -
The Journal of Biological Chemistry Nov 1997Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against acute toxicity of...
Butylated hydroxyanisole and its metabolite tert-butylhydroquinone differentially regulate mitogen-activated protein kinases. The role of oxidative stress in the activation of mitogen-activated protein kinases by phenolic antioxidants.
Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, and especially its potential tumor-promoting activities. Understanding the molecular basis underlying these diverse biological actions of BHA is thus of great importance. Here we demonstrate that BHA is capable of activating distinct mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 2 (ERK2), and c-Jun N-terminal kinase 1 (JNK1). Activation of ERK2 by BHA was rapid and transient, whereas the JNK1 activation was relatively delayed and persistent. A major metabolite of BHA, tert-butylhydroquinone (tBHQ), also activated ERK2 but weakly stimulated JNK1 activity. Furthermore, tBHQ activation of ERK2 was late and prolonged, showing a kinetics different from that induced by BHA. ERK2 activation by both compounds required the involvement of an upstream signaling kinase MAPK/ERK kinase (MEK), as evidenced by the inhibitory effect of a MEK inhibitor, PD98059. Pretreatment with N-acetyl-L-cysteine, glutathione, or vitamin E attenuated ERK2 but not JNK1 activation by BHA and tBHQ. Modulation of intracellular H2O2 levels by direct addition of catalase or pretreatment with a catalase inhibitor, aminotriazole, also affected BHA- and tBHQ-stimulated ERK2 activity but not JNK1, indicating the involvement of oxidative stress in the ERK2 activation by these two compounds. However, we did not observe any generation of H2O2 after exposure of cells to BHA or tBHQ using a H2O2-sensitive fluorescent probe, 2',7'-dichlorofluorescein diacetate. Instead, BHA and tBHQ substantially reduced the amount of intracellular H2O2. Furthermore, BHA and tBHQ activation of ERK2 was strongly inhibited by ascorbic acid and a peroxidase inhibitor, sodium azide, suggesting the potential role of phenoxyl radicals and/or their derivatives. Taken together, our results indicate that (i) BHA and its metabolite tBHQ differentially regulate MAPK pathways, and (ii) oxidative stress due to the generation of reactive intermediates, possibly phenoxyl radicals but not H2O2, is responsible for the ERK2 activation by BHA and tBHQ, whereas the JNK1 activation may require a distinct yet unknown mechanism.
Topics: Amitrole; Antioxidants; Ascorbic Acid; Butylated Hydroxyanisole; Calcium-Calmodulin-Dependent Protein Kinases; Catalase; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Flow Cytometry; Free Radical Scavengers; HeLa Cells; Humans; Hydrogen Peroxide; Hydroquinones; Oxidative Stress; Reactive Oxygen Species; Signal Transduction; Tumor Cells, Cultured
PubMed: 9360968
DOI: 10.1074/jbc.272.46.28962 -
Pharmaceutical Biology Dec 2021species are prolific sources of bioactive secondary metabolites known especially for their antimicrobial and anticancer activities.
CONTEXT
species are prolific sources of bioactive secondary metabolites known especially for their antimicrobial and anticancer activities.
OBJECTIVE
This study sought to isolate and characterize antioxidant molecules biosynthesized by sp. KTM18. The antioxidant potential of an isolated compound and its toxicity were accessed.
MATERIALS AND METHODS
The compound was purified using bioassay-guided chromatography techniques. Nuclear magnetic resonance (NMR) experiments were carried out for structure elucidation. The antioxidant potential of the isolated compound was determined using DPPH free radical scavenging assay. The toxicity of the isolated compound was measured using a brine shrimp lethality (BSL) assay.
RESULTS
Ethyl acetate extract of sp. KTM18 showed more than 90% inhibition of DPPH free radical at 50 µg/mL of the test concentration. These data were the strongest among 13 isolates (KTM12-KTM24). The active molecule was isolated and characterized as maculosin (molecular formula, CHNO as determined by the [M + H] peak at 261.1259). The DPPH free radical scavenging activity of pure maculosin was higher (IC, 2.16 ± 0.05 µg/mL) than that of commercial butylated hydroxyanisole (BHA) (IC, 4.8 ± 0.05 µg/mL). No toxicity was observed for maculosin (LD, <128 µg/mL) in brine shrimp lethality assay (BSLA) up to the compound's antioxidant activity (IC) concentration range. The commercial standard, berberine chloride, showed toxicity in BSLA with an LD value of 8.63 ± 0.15 µg/mL.
CONCLUSIONS
Maculosin may be a leading drug candidate in various cosmetic and therapeutic applications owing to its strong antioxidant and non-toxic properties.
Topics: Animals; Antioxidants; Artemia; Biphenyl Compounds; Free Radical Scavengers; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Peptides, Cyclic; Picrates; Piperazines; Secondary Metabolism; Streptomyces; Toxicity Tests
PubMed: 34236286
DOI: 10.1080/13880209.2021.1946091 -
Molecules (Basel, Switzerland) May 2022Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in...
Coumestrol (3,9-dihydroxy-6-benzofuran [3,2-c] chromenone) as a phytoestrogen and polyphenolic compound is a member of the Coumestans family and is quite common in plants. In this study, antiglaucoma, antidiabetic, anticholinergic, and antioxidant effects of Coumestrol were evaluated and compared with standards. To determine the antioxidant activity of coumestrol, several methods-namely N,N-dimethyl-p-phenylenediamine dihydrochloride radical (DMPD)-scavenging activity, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonate) radical (ABTS)-scavenging activity, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH)-scavenging activity, potassium ferric cyanide reduction ability, and cupric ion (Cu)-reducing activity-were performed. Butylated hydroxyanisole (BHA), Trolox, α-Tocopherol, and butylated hydroxytoluene (BHT) were used as the reference antioxidants for comparison. Coumestrol scavenged the DPPH radical with an IC value of 25.95 μg/mL (r: 0.9005) while BHA, BHT, Trolox, and α-Tocopherol demonstrated IC values of 10.10, 25.95, 7.059, and 11.31 μg/mL, respectively. When these results evaluated, Coumestrol had similar DPPH-scavenging effect to BHT and lower better than Trolox, BHA and α-tocopherol. In addition, the inhibition effects of Coumestrol were tested against the metabolic enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase II (CA II), and α-glycosidase, which are associated with some global diseases such as Alzheimer's disease (AD), glaucoma, and diabetes. Coumestrol exhibited K values of 10.25 ± 1.94, 5.99 ± 1.79, 25.41 ± 1.10, and 30.56 ± 3.36 nM towards these enzymes, respectively.
Topics: Acetylcholinesterase; Antioxidants; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butyrylcholinesterase; Carbonic Anhydrases; Coumestrol; Free Radical Scavengers; Glycoside Hydrolases; alpha-Tocopherol
PubMed: 35630566
DOI: 10.3390/molecules27103091 -
Talanta May 2010A simple electrochemical method was developed for the single and simultaneous determination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in food...
Simultaneous determination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in food samples using a carbon composite electrode modified with Cu(3)(PO(4))(2) immobilized in polyester resin.
A simple electrochemical method was developed for the single and simultaneous determination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in food samples using square-wave voltammetry (SWV). A carbon composite electrode modified (MCCE) with copper (II) phosphate immobilized in a polyester resin was proposed. The modified electrode allowed the detection of BHA and BHT at potentials lower than those observed at unmodified electrodes. A separation of about 430mV between the peak oxidation potentials of BHA and BHT in binary mixtures was obtained. The calibration curves for the simultaneous determination of BHA and BHT demonstrated an excellent linear response in the range from 3.4x10(-7) to 4.1x10(-5)molL(-1) for both compounds. The detection limits for the simultaneous determination of BHA and BHT were 7.2x10(-8) and 9.3x10(-8)molL(-1), respectively. In addition, the stability and repeatability of the electrode were determined. The proposed method was successfully applied in the simultaneous determination of BHA and BHT in several food samples, and the results obtained were found to be similar to those obtained using the high performance liquid chromatography method with agreement at 95% confidence level.
Topics: Antioxidants; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carbon; Chemistry Techniques, Analytical; Chromatography, High Pressure Liquid; Copper; Electrochemistry; Electrodes; Food Analysis; Food Contamination; Models, Chemical; Phenols; Polyesters
PubMed: 20298900
DOI: 10.1016/j.talanta.2010.02.004 -
Antioxidants (Basel, Switzerland) Jan 2023A natural antioxidant, widely spread in plants, chlorogenic acid (CGA), can be lipophilized through a heterogeneous, non-enzymatic, catalytic process. Thus, sulfonic...
A natural antioxidant, widely spread in plants, chlorogenic acid (CGA), can be lipophilized through a heterogeneous, non-enzymatic, catalytic process. Thus, sulfonic resins under no solvent conditions allow to obtain a series of esters in up to 93% yield through reaction of CGA with fatty alcohols of different chain length. The reaction takes place in one single step under mild conditions with conversions up to 96% and selectivity up to 99%. Product recovery in high purity was very easy and the esters obtained were fully characterized with spectroscopic techniques and through the DPPH test to verify the preservation of antioxidant activity. According to this test, all of them showed increased activity with respect to the parent acid and anyway higher than butylated hydroxyanisole. An in-silico method also suggested their very low toxicity. The increased lipophilicity of the esters allows their formulation in cosmetic and nutraceutic lipid-based products.
PubMed: 36829780
DOI: 10.3390/antiox12020218 -
Preventive Nutrition and Food Science Sep 2020Hyperlipidemia and oxidative stress are risk factors for atherosclerosis. In this study, we investigated the hypolipidemic and anti-lipoprotein oxidation activities of...
Phenolic-Rich Extract from Almond () Hulls Improves Lipid Metabolism in Triton WR-1339 and High-Fat Diet-Induced Hyperlipidemic Mice and Prevents Lipoprotein Oxidation: A Comparison with Fenofibrate and Butylated Hydroxyanisole.
Hyperlipidemia and oxidative stress are risk factors for atherosclerosis. In this study, we investigated the hypolipidemic and anti-lipoprotein oxidation activities of polyphenol-rich extracts from almond hulls using Triton WR-1339 and high-fat diet-induced hyperlipemic mice as experimental models. We demonstrated that the almond hull extract significantly reduced total cholesterol, triglycerides and low-density lipoprotein-related plasma cholesterol (LDL-C) in the two experimental models of hyperlipidemia, but significantly increased high-density lipoprotein-related plasma cholesterol (HDL-C). Another beneficial effect of the extract was its ability to reduce the atherogenic index and LDL-C/HDL-C ratio. However, the extract exhibited effective antiradical activity against 2,2-diphenyl-1-picrylhydrazyl and significantly protected lipoprotein-rich plasma from mice against oxidation induced by copper ion. The extract contains 342.63±3.44 mg/g total phenolics, 144.67±6.83 mg/g tannins, and 20.66±0.92 mg/g flavonoids. These finding indicate that almond hulls contain polar products able to lower plasma lipid concentrations and which might be beneficial for the treatment of hyperlipidemia and prevention of atherosclerosis.
PubMed: 33083374
DOI: 10.3746/pnf.2020.25.3.254 -
Asian Pacific Journal of Tropical... Jan 2014To investigate the antioxidant efficacy of a biologically active diterpenoid compound sugiol isolated from Metasequoia glyptostroboides (M. glyptostroboides) in various...
OBJECTIVE
To investigate the antioxidant efficacy of a biologically active diterpenoid compound sugiol isolated from Metasequoia glyptostroboides (M. glyptostroboides) in various antioxidant models.
METHODS
An abietane type diterpenoid sugiol, isolated from ethyl acetate extract of M. glyptostroboides cones, was analyzed for its antioxidant efficacy as reducing power ability and lipid peroxidation inhibition as well as its ability to scavenge free radicals such as 1,1-diphenyl-2-picryl hydrazyl, nitric oxide, superoxide and hydroxyl radicals.
RESULTS
The sugiol showed significant and concentration-dependent antioxidant and free radical scavenging activities. Consequently, the sugiol exerted lipid peroxidation inhibitory effect by 76.5% as compared to α-tocopherol (80.13%) and butylated hydroxyanisole (76.59%). In addition, the sugiol had significant scavenging activities of 1,1-diphenyl-2-picryl hydrazyl, nitric oxide, superoxide and hydroxyl free radicals in a concentration-dependent manner by 78.83%, 72.42%, 72.99% and 85.04%, when compared to the standard compound ascorbic acid (81.69%, 74.62%, 73.00% and 73.79%) and α-tocopherol/butylated hydroxyanisole (84.09%, 78.61%, 74.45% and 70.02%), respectively.
CONCLUSIONS
These findings justify the biological and traditional uses of M. glyptostroboides or its secondary metabolites as confirmed by its promising antioxidant efficacy.
Topics: Analysis of Variance; Animals; Antioxidants; Biphenyl Compounds; Brain Chemistry; Cattle; Cupressaceae; Diterpenes; Free Radical Scavengers; Lipid Peroxidation; Phospholipids; Picrates; Seeds
PubMed: 24418075
DOI: 10.1016/S1995-7645(13)60183-2