Flavonol

/ALTERNATIVE and IN VITRO TESTS/ ...This study ... investigated the cytotoxicities of flavone (F01), 3-hydroxyflavone (F02), 6- hydroxyflavone (F03), 7-hydroxyflavone (F04), 3,6-dihydroxyflavone (F05), 5,7-dihydroxyflavone (F06) and 5,6,7-trihydroxyflavone (F07) to human cancer cells including P-glycoprotein (Pgp)-expressing HCT15 cells and its multidrug resistant subline, HCT15/CL02 cells. ... Tthe effects of those flavonoids on the cell cycle of these cancer cells /was also examined/. HCT15/CL02 cells did not reveal resistance to all the flavonoids tested in comparison with HCT15 cells. In cell cycle analysis, all the flavonoids tested, except F01 and F04, reduced the G0/G1 population of SF295 cells at growth inhibitory concentrations, and increased G2/M (F02, F03 and F06) or S (F05 and F07) populations. In addition, F02 and F03 decreased the G2/M and G0/G1 population, and increased the S and G2/M population in HCT15 cells, respectively. Meanwhile, in HCT15/CL02 cells, F02 and F03 decreased the G0/G1 populations and increased the S population. ...

/ALTERNATIVE and IN VITRO TESTS/ The cytotoxicity of flavonoids, including ... 3-hydroxyflavone ... toward ... human lung embryonic fibroblasts (TIG-1) and human umbilical vein endothelial (HUVE) cells, was examined. When these normal human cells were incubated with each flavonoid in culture medium for 24 h, some of the flavonoids showed considerable cytotoxicity at relatively high concentrations and in a dose-dependent manner. 3-Hydroxyflavone, luteolin, and apigenin were more toxic toward TIG-1 cells than the other flavonoids, and luteolin, 3-hydroxyflavone, and quercetin were more toxic toward HUVE cells. HUVE cells were more vulnerable to flavonoid cytotoxicity than TIG-1 cells. ...

/ALTERNATIVE and IN VITRO TESTS/ ... A series of ten structurally related flavonoids were evaluated for their effect on methoxyresorufin O-demethylase (MROD) activity in human liver microsomes. All compounds inhibited this cytochrome P450 1A2 (CYP1A2) mediated activity. 3,5,7-Trihydoxyflavone (galangin) was the most potent inhibitor, followed by 3-hydroxyflavone and flavone. The relative inhibitory potency of flavonoids is related to their structures. The results suggest that flavonoids may modulate pharmacological and toxicological effects mediated by CYP1A2.

/ALTERNATIVE and IN VITRO TESTS/ Various flavones, flavonols (3-hydroxyflavones) and isoprenoid-substituted flavones (flavonols) were investigated for their cytotoxic activity. Most of these compounds were more cytotoxic against human oral squamous cell carcinoma and salivary gland tumor cell lines than human gingival fibroblasts. ... Flavonoids induced apoptotic cell death characterized by DNA fragmentation (as identified by TUNEL method) and activation of caspase(s) (as identified by degradation products of cytokeratin 18 with M30 monoclonal antibody). ESR spectroscopy revealed that higher concentrations of flavonoids produced radicals under alkaline conditions. However, not all of them enhanced the radical intensity of sodium ascorbate, suggesting that the redox potential of flavonoids differs considerably from samples to samples. Catalase failed to eliminate the cytotoxic activity of flavonoids, reducing the possibility of the involvement of hydrogen peroxide for the cytotoxicity induction by them.

For more Human Toxicity Excerpts (Complete) data for 3-HYDROXYFLAVONE (6 total), please visit the HSDB record page.

/ALTERNATIVE and IN VITRO TESTS/ Sixteen flavonoids were tested for a positive inotropic effect (PIE) on guinea-pig papillary muscle paced at 0.2 Hz in a Krebs-Henseleit solution at 30 degrees C. The structure-activity relationship was investigated by determining both the pD2 value and the intrinsic activity in the case of ten flavonols, three flavones, one flavanone and two catechins. Quercetin showed the most potent intrinsic activity, and produced the strongest inotropic responses among the 16 compounds. The relative order of potency of the tested flavonoids was quercetin > morin = kaempferol = HEPTA > luteolin = apigenin > natsudaidain = fisetin = galangin. Those that did not produce any PIE were 3-hydroxyflavone, flavone, glycosides of quercetin (rutin and hyperin), flavanones (naringenin) and catechins. With respect to the essential flavonoid nucleus for PIE development, the presence of a hydroxy group at C-4', an alpha, beta-unsaturated ketone on the C-ring and a reasonable lipophilic moiety in the molecule are required. Pharmacological analyses suggest that there is a common mechanism for the PIE and it is cyclic AMP dependent.

/ALTERNATIVE and IN VITRO TESTS/ The suppressive effect of flavonoids on the cytotoxicity of linoleic acid hydroperoxide (LOOH) toward rat phenochromocytoma PC12 cells was examined. The extent of cytotoxicity was shown on the basis of % survival determined by the trypan blue exclusion test. On preincubation of cells with either 3-hydroxyflavone, quercetin, or luteolin prior to LOOH exposure, the cytotoxicity was considerably suppressed. In contrast, on coincubation of cells with either eriodictyol, quercetin, kaempherol, luteolin, or 3-hydroxyflavone and LOOH, it was markedly suppressed. Regardless of incubation conditions, quercetin, 3-hydroxyflavone, and luteolin were thus more effective as protective agents against the cytotoxicity than the other flavonoids. These flavonoids further showed a suppressive effect on coincubation rather than on preincubation. ..

/ALTERNATIVE and IN VITRO TESTS/ Rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK), assayed using the synthetic peptide substrate, LRRASLG, is inhibited by a range of plant-derived flavonoids. In general, maximal inhibitory effectiveness (IC50 values 1 to 2 uM) requires 2,3-unsaturation and polyhydroxylation involving at least two of the three flavonoid rings. 3-Hydroxyflavone (IC50 value 4 uM), 3,5,7,2',4'-pentahydroxyflavone (IC50 = 10 uM) and 5,7,4'-trihydroxyflavone (IC50 = 7 uM) represent somewhat less active variations from this pattern. Flavonoid O-methylation or O-glycosylation greatly decreases inhibitory effectiveness, as does 2,3-saturation. Various flavonoid-related compounds, notably gossypol (IC50 = 10 uM), also inhibit cAK. Flavonoids and related compounds are in general much better inhibitors of cAK than of avian Ca(2+)-calmodulin-dependent myosin light chain kinase or of plant Ca(2+)-dependent protein kinase. Tricetin (IC50 = 1 uM) inhibits cAK in a fashion that is non-competitive with respect to both peptide substrate and ATP (Ki value 0.7 uM). When histone III-S is used as a substrate, inhibition of cAK requires much higher flavonoid concentrations.

/ALTERNATIVE and IN VITRO TESTS/ in vitro studies, via absorption and fluorescence spectroscopy, /are reported/ on the effects of several flavonoids (namely fisetin, quercetin, chrysin, morin, and 3-hydroxyflavone, 3-HF) in goat RBC membranes. ... Binding of the flavonoids to the RBC membranes significantly inhibits lipid peroxidation, and at the same time enhances their integrity against hypotonic lysis. Interestingly, the antioxidant and antihemolytic activities are found to be crucially dependent on the locations of the flavonoids in the membrane matrix as revealed by fluorescence studies. Furthermore, we observe that FRET (from membrane protein tryptophans to flavonoids) occurs with significant efficiency indicating that the flavonoid binding sites lie in close proximity to the tryptophan residues in the ghost membrane proteins.

/OTHER TOXICITY INFORMATION/ The inhibition of CYP3A4-mediated oxidation of triazolam and testosterone was assessed in the presence of a selection of known CYP3A4 substrates and inhibitors. Under experimental conditions where the Michaelis-Menten model predicts substrate-independent inhibition ([S] = K(m)), results yielded substrate-dependent inhibition. Moreover, when the same experimental design was extended to a group of structurally similar flavonoids it was observed that flavanone, flavone, 3-hydroxyflavone, and 6-hydroxyflavone (10 uM) activated triazolam metabolism, but inhibited testosterone hydroxylation. ...

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/