curcumin and 2-tert-butylhydroquinone

Certain dioxins, including 2,3,7,8,-tetrachloro-dibenzo-p-dioxin (TCDD), are exogenous ligands for an aryl hydrocarbon receptor (AhR) and induces various drug-metabolizing enzymes. In this study, we examined the effect of curcumin on expression of drug-metabolizing enzymes through the AhR and NF-E2 related factor 2 (Nrf2) pathways. Curcumin dose-dependently inhibited TCDD-induced expression of phase I enzyme cytochrome P450 1A1 (CYP1A1) and phase II enzymes NAD(P)H:quinone oxidoreductase-1 (NQO1) and heme oxygenase 1 (HO-1) but not tert-butyl hydroquinone-induced NQO1 and HO-1, suggesting that curcumin inhibited only AhR pathway, but not Nrf2 one directly. Furthermore, we used 14 curcumin derivatives and obtained the correlation between hydrophobicity of the compounds and suppressive effect against AhR transformation. Results from the quantitative structure active correlative analysis indicated that methoxy groups and β-diketone structure possessing keto-enol tautomerism in curcumin were necessary to inhibit AhR transformation, and the addition of methyl and methoxy group(s) to the curcumin increased the inhibition effect.

Topics: Animals; Cell Line, Tumor; Curcumin; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; Heme Oxygenase-1; Hydrophobic and Hydrophilic Interactions; Hydroquinones; Mice; NAD(P)H Dehydrogenase (Quinone); Phosphorylation; Polychlorinated Dibenzodioxins; Quantitative Structure-Activity Relationship; Receptors, Aryl Hydrocarbon

Substantial studies have shown that curcumin, a dietary compound from turmeric, has beneficial effects on many diseases. However, curcumin rapidly degrades at physiological pH, making it difficult to interpret whether the observed actions of curcumin are from curcumin itself or its degradation products. Therefore, it is important to better understand the mechanisms involved in curcumin degradation and the roles of degradation in its biological actions.. Here, we show that a series of redox active antioxidants with diverse chemical structures, including gallic acid, ascorbate (vitamin C), tert-butylhydroquinone (TBHQ), caffeic acid, rosmarinic acid, and Trolox (a water-soluble analog of vitamin E), dramatically increased curcumin stability in phosphate buffer at physiological pH. When treated in basal cell culture medium in MC38 colon cancer cells, curcumin rapidly degraded with a half-life of several minutes and showed a weak antiproliferative effect; co-addition of antioxidants enhanced stability and antiproliferative effect of curcumin. Finally, co-administration of antioxidant significantly increased plasma level of curcumin in animal models.. Together, these studies strongly suggest that a redox-dependent mechanism plays a critical role in mediating curcumin degradation. In addition, curcumin itself, instead of its degradation products, is largely responsible for the observed biological actions of curcumin.

Topics: Animals; Antioxidants; Ascorbic Acid; Caffeic Acids; Cell Line, Tumor; Cell Proliferation; Chromans; Cinnamates; Curcumin; Depsides; Drug Stability; Gallic Acid; Hydrogen-Ion Concentration; Hydroquinones; Male; Mice; Oxidation-Reduction; Rosmarinic Acid

The active substance of turmeric rhizome (curcumin) was extracted and identified with TLC and NMR. To evaluate the antioxidant efficiency of different concentrations of curcumin (120, 160 and 200 ppm) compared with tert-butylhydroquinone (TBHQ) (120 ppm) and α-tocopherol (200 ppm) at two different temperatures (25°C and 55°C) under dark and light conditions during 90 days, the soybean oil with no added antioxidant was used as a food model, and its fatty acids profile was determined by GC. Results indicated that increasing concentration of curcumin leads to significantly decreased oxidation rates. The soybean oil containing curcumin at 25°C in darkness with the lowest rate of increased peroxide value indicated the same antioxidant activity with α-tocopherol and TBHQ. Moreover, the results of acid value and iodine value indicated that samples with curcumin were more effective in preventing oxidation at both temperatures compared with control. However, light did not have any significant effect.

Topics: alpha-Tocopherol; Antioxidants; Chromatography, Gas; Curcumin; Fatty Acids; Hydroquinones; Nuclear Magnetic Resonance, Biomolecular; Plant Oils; Rhizome; Soybean Oil; Temperature

Antioxidant and oxidative stress effects of prooxidants are generally dose-dependent, and these effects depend on the prooxidant species and cell type. However, the cellular response to oxidant challenge is a complicated interplay of events involving cellular expression of phase II detoxification enzymes and cellular metal metabolism. This study demonstrates the effect of tert-butylhydroquinone (t-BHQ)-induced oxidative stress on MDCK cells. Cell toxicity tests were carried out using the crystal violet (CV) assay with the following prooxidants: t-BHQ, diethyl maleate (DEM), hydrogen peroxide (H(2)O(2)), diquat (DQ) and β-naphthoflavone (β-NF). Except for β-NF, these prooxidants showed dose-dependent cytotoxicity besides the most potent t-BHQ cytotoxicity. Only t-BHQ and DEM caused significant time-dependent expression of ferritin protein as an antioxidant, which segregates Fe(2+), causing the Fenton reaction. t-BHQ and DEM increased formation of lipid peroxidation, but DQ showed a tendency to decrease lipid peroxidation levels. In XTT assay, even when substantial cell death was observed in the CV assay, t-BHQ appeared to increase cell viability by enhancing XTT reduction, likely through the production of NADPH. Although curcumin, which induces cytoprotective phase II enzymes and chelates metal irons, decreased cell viability, it inhibited t-BHQ cytotoxicity. These results indicate that t-BHQ exhibits strong cytotoxicity against MDCK cells, an effect mitigated by curcumin, and that t-BHQ-induced oxidative stress activates the pentose phosphate pathway.

Topics: Animals; Antioxidants; Cell Line; Cell Survival; Curcumin; Dogs; Hydroquinones; Kidney; Lipid Peroxidation; Oxidants; Oxidative Stress

A decrease in GSH levels, the main redox regulator, can be observed in neurodegenerative diseases as well as in schizophrenia. In search for substances able to increase GSH, we evaluated the ability of curcumin (polyphenol), quercetin (flavonoid), and tert-butylhydroquinone (tBHQ) to up-regulate GSH-synthesizing enzymes. The gene expression, activity, and product levels of these enzymes were measured in cultured neurons and astrocytes. In astrocytes, all substances increased GSH levels and the activity of the rate-limiting synthesizing enzyme, glutamate cysteine ligase (GCL). In neurons, curcumin and to a lesser extent tBHQ increased GCL activity and GSH levels, while quercetin decreased GSH and led to cell death. In the two cell types, the gene that showed the greatest increase in its expression was the one coding for the modifier subunit of GCL (GCLM). The increase in mRNA levels of GCLM was 3 to 7-fold higher than that of the catalytic subunit. In astrocytes from GCLM-knock-out mice showing low GSH (-80%) and low GCL activity (-50%), none of the substances succeeded in increasing GSH synthesis. Our results indicate that GCLM is essential for the up-regulation of GCL activity induced by curcumin, quercetin and tBHQ.

Topics: Analysis of Variance; Animals; Antioxidants; Astrocytes; Cell Survival; Cells, Cultured; Cerebral Cortex; Curcumin; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Inhibitors; Gene Expression; Glutamate-Cysteine Ligase; Glutathione; Hydroquinones; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Protein Subunits; Quercetin; Up-Regulation

The gastrointestinal glutathione peroxidase (GI-GPx, GPx2) is a selenoprotein that was suggested to act as barrier against hydroperoxide absorption but has also been implicated in the control of inflammation and malignant growth. In CaCo-2 cells, GI-GPx was induced by t-butyl hydroquinone (tBHQ) and sulforaphane (SFN), i.e., "antioxidants" known to activate the "antioxidant response element" (ARE) via electrophilic thiol modification of Keap1 in the Nrf2/Keap1 system. The functional significance of a putative ARE in the GI-GPx promoter was validated by transcriptional activation of reporter gene constructs upon exposure to electrophiles (tBHQ, SFN, and curcumin) or overexpression of Nrf2 and by reversal of these effects by mutation of the ARE in the promoter and by overexpressed Keap1. Binding of Nrf2 to the ARE sequence in authentic gpx2 was corroborated by chromatin immunoprecipitation. Thus, the presumed natural antioxidants sulforaphane and curcumin may exert their anti-inflammatory and anticarcinogenic effects not only by induction of phase 2 enzymes but also by the up-regulation of the selenoprotein GI-GPx.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antioxidants; Cell Line, Tumor; Curcumin; DNA-Binding Proteins; Gene Expression Regulation; Genes, Reporter; Glutathione Peroxidase; Humans; Hydroquinones; Intracellular Signaling Peptides and Proteins; Isothiocyanates; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Promoter Regions, Genetic; Protein Binding; Proteins; Response Elements; Sulfoxides; Thiocyanates; Trans-Activators

We determined whether an oral administration of the synthetic antioxidant, tert-butylhydroquinone (TBHQ), or the naturally occurring lipoxygenase inhibitor, curcumin, to rats would provide protection against the diabetogenic effect of streptozotocin (STZ). Male Sprague-Dawley rats were fed on an AIN-76-based purified diet containing 0.0028% TBHQ or on the purified diet with a daily intragastric administration of curcumin (200 mg/kg of body weight) for one week while receiving intravenously administered STZ. The rats fed on the TBHQ-containing diet were resistant to diabetes development when compared with the rats fed on the TBHQ-free diet and had a higher body weight gain and lower serum glucose concentration. Glucose-stimulated insulin secretion from the pancreatic islet in the rats that had received TBHQ was higher than that in the control rats. The rats receiving curcumin showed no beneficial effect on these diabetic symptoms. These findings provide direct evidence for the suggestion that dietary supplementation of an antioxidant may exert a preventive effect on the diabetogenic action of free-radical producers.

Topics: Administration, Oral; Animals; Antioxidants; Blood Glucose; Curcumin; Diabetes Mellitus, Experimental; Free Radicals; Hydroquinones; In Vitro Techniques; Insulin; Insulin Secretion; Islets of Langerhans; Lipoxygenase Inhibitors; Male; Rats; Rats, Sprague-Dawley; Streptozocin; Triglycerides