luteolin may increase human lifespan - (long)

Doug Skrecky (oberon@vcn.bc.ca)
Fri, 21 May 1999 21:06:08 -0700 (PDT)

Citations: 1-25
<1>

Authors
Takahashi T. Kobori M. Shinmoto H. Tsushida T. Institution
Iwate Industrial Research Institute, Japan. Title
Structure-activity relationships of flavonoids and the induction of granulocytic- or monocytic-differentiation in HL60 human myeloid leukemia cells.
Source
Bioscience, Biotechnology & Biochemistry. 62(11):2199-204, 1998 Nov. Abstract
The flavones apigenin and luteolin strongly inhibited the growth of HL60 cells and induced morphological differentiation into granulocytes. The flavonol quercetin inhibited the cell growth and induced a differentiation marker, i.e., NBT reducing ability. However quercetin-treated cells were not morphologically differentiated into granulocytes. The chalcone phloretin weakly induced NBT reducing ability and a marker of monocytic differentiation alpha-naphthyl butyrate esterase activity in the cells. Quercetin and phloretin appeared to induce the differentiation of HL60 cells into monocytes. The proportion of alpha-naphthyl butyrate esterase-positive cells induced by genistein was less than that of the NBT-positive cells. Some of the nuclei in genistein-treated HL60 cells morphologically changed. Genistein must have induced both granulocytic and monocytic differentiation of HL60 cells. The flavonols galangin and kaempferol, which had fewer hydroxyl group(s) in the B-ring than quercetin, and the flavanone naringenin inhibited the growth but did not induce the differentiation of HL60 cells.

<2>

Authors
Brown JE. Rice-Evans CA.
Institution
International Antioxidant Research Centre, UMDS-Guy's Hospital, London, UK. Title
Luteolin-rich artichoke extract protects low density lipoprotein from oxidation in vitro.
Source
Free Radical Research. 29(3):247-55, 1998 Sep. Abstract
Flavonoids represent a diverse group of phytochemicals which possess the capacity to act as antioxidants in vitro. This study examined the free radical scavenging properties of a luteolin-rich artichoke extract and some of its pure flavonoid constituents by assessing their ability to prevent Cu2+-mediated LDL oxidation. Artichoke extract retarded LDL oxidation in a dose-dependent manner as measured by a prolongation of the lag phase to conjugated diene formation, a decrease in the rate of propagation and a sparing of endogenous LDL alpha-tocopherol during oxidation. The pure aglycone, luteolin (1 microM), demonstrated an efficacy similar to that of 20 microg/ml artichoke extract in inhibiting lipid peroxidation. Luteolin-7-O-glucoside, one of the glycosylated forms in the diet, also demonstrated a dose-dependent reduction of LDL oxidation that was less effective than that of luteolin. Studies of the copper-chelating properties of luteolin-7-O-glucoside and luteolin suggest a potential role for chelation in the antioxidative effects of artichoke extract. Overall, the results demonstrate that the antioxidant activity of the artichoke extract relates in part to its constituent flavonoids which act as hydrogen donors and metal ion chelators, and the effectiveness is further influenced by their partitioning between aqueous and lipophilic phases.

<3>

Authors
Shimoi K. Okada H. Furugori M. Goda T. Takase S. Suzuki M. Hara Y. Yamamoto H. Kinae N.
Institution
School of Food and Nutritional Sciences, University of Shizuoka, Japan. shimoi@fns1.u-shizuoka-ken.ac.jp
Title
Intestinal absorption of luteolin and
luteolin 7-O-beta-glucoside in rats and humans. Source
FEBS Letters. 438(3):220-4, 1998 Nov 6. Abstract
In this study, we investigated the intestinal absorption of luteolin and luteolin 7-O-beta-glucoside in rats by HPLC. The absorption analysis using rat everted small intestine demonstrated that luteolin was converted to glucuronides during passing through the intestinal mucosa and that luteolin 7-O-beta-glucoside was absorbed after hydrolysis to luteolin. Free luteolin, its conjugates and methylated conjugates were present in rat plasma after dosing. This suggests that some luteolin can escape the intestinal conjugation and the hepatic sulfation/methylation. LC/MS analysis showed that the main conjugate which circulates in the blood was a monoglucuronide of the unchanged aglycone. Luteolin in propyleneglycol was absorbed more rapidly than that in 0.5% carboxymethyl cellulose. The plasma concentration of luteolin and its conjugates reached the highest level 15 min and 30 min after dosing with luteolin in propyleneglycol, respectively. HPLC analysis also allowed us to demonstrate the presence of free luteolin and its monoglucuronide in human serum after ingestion of luteolin.

<4>

Authors
Noroozi M. Angerson WJ. Lean ME.
Institution
Department of Human Nutrition, Glasgow University, Royal Infirmary, United Kingdom.
Title
Effects of flavonoids and vitamin C on oxidative DNA damage to human lymphocytes.
Source
American Journal of Clinical Nutrition. 67(6):1210-8, 1998 Jun. Abstract
This study assessed the antioxidant potencies of several widespread dietary flavonoids across a range of concentrations and compared with vitamin C as a positive control. The antioxidant effects of pretreatment with flavonoids and vitamin C, at standardized concentrations (7.6, 23.2, 93, and 279.4 micromol/L), on oxygen radical-generated DNA damage from hydrogen peroxide (100 micromol/L) in human lymphocytes were examined by using the single-cell gel electrophoresis assay (comet assay). Pretreatment with all flavonoids and vitamin C produced dose-dependent reductions in oxidative DNA damage. At a concentration of 279 micromol/L, they were ranked in decreasing order of potency as follows: luteolin (9% of damage from unopposed hydrogen peroxide), myricetin (10%), quercetin (22%), kaempferol (32%), quercitrin (quercetin-3-L-rhamnoside) (45%), apigenin (59%), quercetin-3-glucoside (62%), rutin (quercetin-3-beta-D-rutinoside) (82%), and vitamin C (78%). The protective effect of vitamin C against DNA damage at this concentration was significantly less than that of all the flavonoids except apigenin, quercetin-3-glucoside, and rutin. The ranking was similar with estimated ED50 (concentration to produce 50% protection) values. The protective effect of quercetin and vitamin C at a concentration of 23.2 micromol/L was found to be additive (quercetin: 71% of maximal DNA damage from unopposed hydrogen peroxide; vitamin C: 83%; both in combination: 62%). These data suggest that the free flavonoids are more protective than the conjugated flavonoids (eg, quercetin compared with its conjugate quercetin-3-glucoside, P < 0.001). Data are also consistent with the hypothesis that antioxidant activity of free flavonoids is related to the number and position of hydroxyl groups.

<5>

Authors
Wang C. Kurzer MS.
Institution
Department of Food Science and Nutrition, University of Minnesota, St. Paul 55108, USA.
Title
Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells.
Source
Nutrition & Cancer. 28(3):236-47, 1997. Abstract
Thirteen isoflavonoids, flavonoids, and lignans, including some known phytoestrogens, were evaluated for their effects on DNA synthesis in estrogen-dependent (MCF-7) and -independent (MDA-MB-231) human breast cancer cells. Treatment for 24 hours with most of the compounds at 20-80 microM sharply inhibited DNA synthesis in MDA-MB-231 cells. In MCF-7 cells, on the other hand, biphasic effects were seen. At 0.1-10 microM, coumestrol, genistein, biochanin A, apigenin, luteolin, kaempferol, and enterolactone induced DNA synthesis 150-235% and, at 20-90 microM, inhibited DNA synthesis by 50%. Treatment of MCF-7 cells for 10 days with genistein or coumestrol showed continuous stimulation of DNA synthesis at low concentrations. Time-course experiments with genistein in MCF-7 cells showed effects to be reversed by 48-hour withdrawal of genistein at most concentrations. Induction of DNA synthesis in MCF-7 cells, but not in MDA-MB-231 cells, is consistent with an estrogenic effect of these compounds. Inhibition of estrogen-dependent and -independent breast cancer cells at high concentrations suggests additional mechanisms independent of the estrogen receptor. The current focus on the role of phytoestrogens in cancer prevention must take into account the biphasic effects observed in this study, showing inhibition of DNA synthesis at high concentrations but induction at concentrations close to probable levels in humans.

<6>

Unique Identifier
97407568
Authors
Agullo G. Gamet-Payrastre L. Manenti S. Viala C. Remesy C. Chap H. Payrastre B.
Institution
Laboratoire des Maladies Metaboliques, INRA de Theix, Ceyrat, France. Title
Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition.
Source
Biochemical Pharmacology. 53(11):1649-57, 1997 Jun 1. Abstract
Depending on their structure, flavonoids display more or less potent inhibitory effects on the growth and proliferation of certain malignant cells in vitro, and these effects are thought to be due to inhibition of various enzymes. We investigated the inhibitory action of fourteen flavonoids of different chemical classes on phosphatidylinositol 3-kinase alpha (PI 3-kinase alpha) activity, an enzyme recently shown to play an important role in signal transduction and cell transformation. Of the fourteen flavonoids tested, myricetin was the most potent PI 3-kinase inhibitor (IC50 = 1.8 microM), while luteolin and apigenin were also effective inhibitors, with IC50 values of 8 and 12 microM, respectively. Fisetin and quercetin, as previously reported, were also found to significantly inhibit PI 3-kinase activity. The same flavonoids were also analyzed for inhibition of epidermal growth factor receptor (EGF-R), intrinsic tyrosine kinase and bovine brain protein kinase C (PKC). At elevated doses, some of these flavonoids were found to also cause significant inhibition of PKC and tyrosine kinase activity of EGF-R. A structure-activity study indicated that the position, number and substitution of the hydroxyl group of the B ring, and saturation of the C2-C3 bond are important factors affecting flavonoid inhibition of PI 3-kinase. They may also play a significant role in specificity of inhibition and could help to provide a basis for the further design of specific inhibitors of this lipid kinase. Finally, possible relationships between the antitumoral properties of these flavonoids and their biological activities are discussed.

<7>

Authors
Fotsis T. Pepper MS. Aktas E. Breit S. Rasku S. Adlercreutz H. Wahala K. Montesano R. Schweigerer L.
Institution
Division of Hematology and Oncology, Children's Hospital, Ruprecht-Karls University, Heidelberg, Germany. thfotsis@cc.uoi.gr Title
Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro angiogenesis.
Source
Cancer Research. 57(14):2916-21, 1997 Jul 15. Abstract
Consumption of a plant-based diet can prevent the development and progression of chronic diseases associated with extensive neovascularization, including solid malignant tumors. In previous studies, we have shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell proliferation and in vitro angiogenesis. In the present study, we report that certain structurally related flavonoids are more potent inhibitors than genistein. Indeed, 3-hydroxyflavone, 3',4'-dihydroxyflavone, 2',3'-dihydroxyflavone, fisetin, apigenin, and luteolin inhibited the proliferation of normal and tumor cells, as well as in vitro angiogenesis, at half-maximal concentrations in the low micromolar range. We have previously demonstrated that genistein concentrations in the urine of subjects consuming a plant-based diet is 30-fold higher than in subjects consuming a traditional Western diet. The wider distribution and the more abundant presence of flavonoids in the plant kingdom, together with the present results, suggest that flavonoids may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumors.

<8>

Authors
Sadzuka Y. Sugiyama T. Shimoi K. Kinae N. Hirota S. Institution
School of Pharmaceutical Sciences, University of Shizuoka, Yada, Japan. Title
Protective effect of flavonoids on doxorubicin-induced cardiotoxicity. Source
Toxicology Letters. 92(1):1-7, 1997 Jun 16. Abstract
We have examined the effect of alpha G-Rutin and luteolin on doxorubicin (DOX) toxicity in mice. In the heart, the lipid peroxide level, increased to 1.5 times of the normal level induced by DOX, decreased to the normal level after treatment with alpha G-Rutin or luteolin (i.p.). Glutathione peroxidase (GSHpx) activity, decreased to 73% of normal activity after DOX treatment, was shown to recover by the combined flavonoids. The lipid peroxide level in bone marrow cells increased to 5.9 times of the normal level by DOX treatment, whereas this level in the extra bone marrow cells did not change by treatment with DOX. The combination of alpha G-Rutin and luteolin with DOX significantly inhibited the DOX induced-increment of the lipid peroxide level in bone marrow cells. Flavonoids have also reduced the effect of DOX toxicity by oral administration. It is suggested that it is possible to reduce DOX toxicity by the intake of food including flavonoids. In NADPH-dependent lipid peroxidation, alpha G-Rutin and luteolin showed concentration-dependent inhibition. Therefore, we considered that the reduction effect of DOX toxicity by flavonoids was caused by antioxidative action and other effect of the flavonoids.

<9>

Authors
Edenharder R. Tang X.
Institution
Department of Hygiene and Environmental Medicine, University of Mainz, Germany.
Title
Inhibition of the mutagenicity of 2-nitrofluorene, 3-nitrofluoranthene and 1-nitropyrene by flavonoids, coumarins, quinones and other phenolic compounds.
Source
Food & Chemical Toxicology. 35(3-4):357-72, 1997 Mar-Apr. Abstract
When 56 flavonoids, 32 coumarins, five naphthoquinones, 12 anthraquinones and five structurally-related compounds were tested for their antimutagenic potencies with respect to mutagenicities induced by 2-nitrofluorene (2-NF), 3-nitrofluoranthene (3-NFA) and 1-nitropyrene (1-NP) in Salmonella typhimurium TA98 distinct structure-activity relationships were detected. First, the tetracyclic nitroarenes 3-NFA and 1-NP were in general more effectively antagonized by potent antimutagenic flavonoids and coumarins than the tricyclic 2-NF, while there were only minor differences with quinones. Secondly, antimutagenicity of natural compounds of plant origin correlated with the aglyconic nature 10 of a total of 15 glycosides were inactive, four flavonoid glycosides exerted antimutagenicity but to a distinctly lower degree than the corresponding aglycones. Thirdly, within flavonoids, coumarins and anthraquinones positive correlations were found between antimutagenic potency and the polarity of a molecule with the existence of an optimum of activity within flavonols and anthraquinones. However, polarity seemed to be unimportant within the chalcone and naphthoquinone series. Among flavonoids, the parent compounds flavone and flavanone were inactive, but all flavones and many flavonoids with phenolic hydroxyl groups exerted antimutagenicity. Antimutagenic potency reached a maximum with the presence of four hydroxyl functions-luteolin, kaempferol-though the position of hydroxyls was also a determinant of antimutagenic potency. Methylation of phenolic hydroxyl groups, however, always reduced antimutagenicity. A carbonyl group at carbon 4 was essential for antimutagenicity: two catechins and anthocyanidins each were inactive. On the other hand, ring C of the flavane nucleus was not essential for antimutagenicity: chalcones and dihydrochalcones were potent antimutagens. Among coumarins, the parent compound showed antimutagenicity against 1-NP and 3-NFA, although dihydrocoumarin, methylcoumarins and compounds with bulky substituents were inactive. Otherwise, antimutagenic activity depended on the presence of polar hydroxyl, amino or carboxyl groups at carbons 3, 4 or 7 but was diminished by interactions of hydroxyl groups vicinal to carbon 7. Again, antimutagenic potencies were reduced by alkylation or acetylation. Among furanocoumarins xanthotoxin exerted strong and bergapten moderate antimutagenicity, while psoralen (except against 3-NFA), isopimpinellin and the furanochromanones visnagin and khellin were inactive. Among anthraquinones, the principles delineated here were valid again, resulting in potent antimutagenicity of most phenolic compounds and inactivity of anthraquinone itself. Among compounds structurally related to anthraquinones, anthrone, acridone and xanthone exerted antimutagenicity, anthrone being the most potent one, while thioxanthone and 9-fluorenone were inactive. All naphthoquinones were potent antimutagens irrespective of the presence of methyl or hydroxyl functions. Plumbagin, 2-methyl-5-hydroxynaphthoquinone, however, showed exceptional antimutagenicity.

<10>

Authors
Pettit GR. Hoard MS. Doubek DL. Schmidt JM. Pettit RK. Tackett LP. Chapuis JC.
Institution
Cancer Research Institute, Arizona State University, Tempe 85287-1604, USA. Title
Antineoplastic agents 338. The cancer cell growth inhibitory. Constituents of Terminalia arjuna (Combretaceae).
Source
Journal of Ethnopharmacology. 53(2):57-63, 1996 Aug. Abstract
By means of bioassay-guided separation methods, the cancer cell growth inhibitory constituents residing in the bark, stem and leaves of the Mauritius medicinal plant Terminalia arjuna (Combretaceae) were examined. The cancer cell line active components were found to be gallic acid, ethyl gallate, and the flavone luteolin. Only gallic acid was previously known to occur in this plant. Luteolin has a well established record of inhibiting various cancer cell lines and may account for most of the rationale underlying the use of T. arjuna in traditional cancer treatments. Luteolin was also found to exhibit specific activity against the pathogenic bacterium Neisseria gonorrhoeae.

<11>

Authors
Shimoi K. Masuda S. Shen B. Furugori M. Kinae N. Institution
Laboratory of Food Hygiene, School of Food and Nutritional Sciences, University of Shizuoka, Japan.
Title
Radioprotective effects of antioxidative plant flavonoids in mice. Source
Mutation Research. 350(1):153-61, 1996 Feb 19. Abstract
Radioprotective effects of tea infusions and plant flavonoids were investigated by using the micronucleus test for anticlastogenic activity and the thiobarbituric acid assay for antioxidative activity. A single gastric intubation of rooibos tea (Aspalathus linearis) infusion at 1 ml per mouse 2 h prior to gama-ray irradiation (1.5 Gy) reduced the frequency of micronucleated reticulocytes (MNRETs). After the fractionation of rooibos tea infusion, the flavonoid fraction was found to be most anticlastogenic and antioxidative. From this fraction, luteolin was isolated as an effective component. Then, anticlastogenic effects of 12 flavonoids containing luteolin and their antioxidative activities against lipid peroxidation by Fenton's reagent were examined. A good correlation (r=0.717) was observed between both activities. Luteolin showed the most effective potency. A gastric intubation of luteolin (10 micromoles/kg) 2 h prior to gamma-ray irradiation (6 Gy) suppressed lipid peroxidation in mouse bone marrow and spleen and a trend of protective effect of luteolin against the decrease of endogenous ascorbic acid in mouse bone marrow after gamma-ray irradiation (3 Gy) was observed. These results suggest that plant flavonoids, which show antioxidative potency in vitro, work as antioxidants in vivo and their radioprotective effects may be attributed to their scavenging potency towards free radicals such as hydroxyl radicals. Therefore, the flavonoids contained in tea, vegetables and fruits seem to be important as antioxidants in the human diet.

<12>

Authors
Zarzuelo A. Jimenez I. Gamez MJ. Utrilla P. Fernadez I. Torres MI. Osuna I.
Institution
Departamento de Farmacologia, Facultad de Farmacia, Universidad de Granada, Spain.
Title
Effects of luteolin 5-O-beta-rutinoside in streptozotocin-induced diabetic rats.
Source
Life Sciences. 58(25):2311-6, 1996.
Abstract
We have investigated the antidiabetic activity of luteolin 5-rutinoside in streptozotocin(STZ)-induced diabetic rats. Treatment for 20 days with 2 mg/kg increased both pancreatic insulin and DNA content. When both luteolin 5-rutinoside (2 mg/kg) and glibenclamide (1 mg/kg) were administered concurrently to STZ-diabetic rats, a marked antidiabetic activity was achieved. This effect was evidenced by a significant decrease in glycemia levels (> 50%), a 2.5-fold increase in insulin blood levels and an increase in body and pancreas weight, compared to the diabetic control group.

<13>

Authors
Shimoi K. Masuda S. Furugori M. Esaki S. Kinae N. Institution
Laboratory of Food Hygiene, School of Food and Nutritional Sciences, University of Shizuoka, Japan.
Title
Radioprotective effect of antioxidative flavonoids in gamma-ray irradiated mice.
Source
Carcinogenesis. 15(11):2669-72, 1994 Nov. Abstract
The anticlastogenic effect of 12 structurally different flavonoids was investigated in whole body gamma-ray irradiated mice. Each flavonoid was administered to ICR male mice by a single gastric intubation (5 mumol/kg) 6 h before gamma-ray irradiation (1.5 Gy) and the frequency of micronucleated reticulocytes (MNRETs) in peripheral blood was determined. In order to elucidate the mechanism of the anticlastogenic effect of these flavonoids, their antioxidative activities were examined by the thiobarbituric acid method using methyl linoleate and Fenton's reagent (Fe2+/H2O2). Of the 12 flavonoids, luteolin had the most marked effect on reducing the frequencies of MNRETs and also inhibiting lipid peroxidation. However, quercetin tetramethylether, which has methoxy groups instead of hydroxyl groups at the 3,7,3',4'-positions, and phloretin with an open C-ring showed the least anticlastogenic and antioxidative activity. A good correlation (r = 0.717, P < 0.01) was observed between the anticlastogenic activity and the antioxidative activity of the 12 flavonoids. These results suggest that the radioprotective effect of flavonoids in mice may be attributed to the hydroxyl radical scavenging potency in a direct or an endogenous enzyme mediated manner.

<14>

Authors
Elangovan V. Sekar N. Govindasamy S. Institution
Department of Biochemistry, University of Madras, India. Title
Chemopreventive potential of dietary bioflavonoids against 20-methylcholanthrene-induced tumorigenesis [published erratum appears in Cancer Lett 1995 Jan 6;88(1):119-20].
Source
Cancer Letters. 87(1):107-13, 1994 Nov 25. Abstract
The effect of dietary supplementation of flavonoidal compounds such as quercetin, rutin, luteolin and (+)-catechin on the incidence of fibrosarcoma induced by 20-methylcholanthrene (20-MC) in male Swiss albino mice was observed. Subcutaneous injection of 20-MC produced 100% tumor incidence and the onset of tumor appeared within 7 weeks, while flavonoid-treated mice (1% quercetin- and luteolin-mixed diets) produced tumors in the 9th week, and the tumor incidences in mice treated with quercetin- and luteolin-mixed diets were 52% and 60%, respectively. Subcutaneous administration of 20-MC along with the flavonoidal compounds (quercetin, luteolin) was found to have significant effect on tumor expression. The compounds rutin and (+)-catechin did not influence tumor expression in both experiments. Elevated levels of lipid peroxides, cytochrome P450 and decreased activity of glutathione-S-transferase (GST) were observed in the tumor bearing animals. Test-diet-treated animals showed reduction in the lipid peroxides and cytochrome P450, and increased activity of GST (P < 0.001). In vitro [3H]thymidine incorporation showed the inhibition of DNA synthesis in fibrosarcoma cells by the flavonoids. The possible mode of action of the flavonoidal compounds may be through their influence on the initiation and promotion phases of the carcinogenic process coupled with enhancement of the detoxification process.

<15>

Authors
Wang C. Makela T. Hase T. Adlercreutz H. Kurzer MS. Institution
Department of Food Science and Nutrition, University of Minnesota, St Paul 55108.
Title
Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes. Source
Journal of Steroid Biochemistry & Molecular Biology. 50(3-4):205-12, 1994 Aug.
Abstract
Lignans and flavonoids are naturally-occurring diphenolic compounds found in high concentrations in whole grains, legumes, fruits and vegetables. Seven lignans and six flavonoids were evaluated for their abilities to inhibit aromatase enzyme activity in a human preadipose cell culture system. The lignan, enterolactone (Enl) and its theoretical precursors, 3'-demethoxy-3O-demethylmatairesinol (DMDM) and didemethoxymatairesinol (DDMM) decreased aromatase enzyme activity, with Ki values of 14.4, 5.0 and 7.3 microM, respectively. The flavonoids, coumestrol, luteolin and kaempferol also decreased aromatase enzyme activity, with Ki values of 1.3, 4.8 and 27.2 microM, respectively. Aminoglutethimide, a pharmaceutical aromatase inhibitor, showed a Ki value of 0.5 microM. Kinetic studies showed the inhibition by all compounds to be competitive. Smaller decreases in aromatase activity were observed with the lignan, enterodiol (End) and its theoretical precursors, O-demethylsecoisolariciresinol (ODSI), demethoxysecoisolariciresinol (DMSI) and didemethylsecoisolariciresinol (DDSI). The flavonoids, O-demethylangolensin (O-Dma), fisetin and morin showed no inhibitory effects. The inhibition of human preadipocyte aromatase activity by lignans and flavonoids suggests a mechanism by which consumption of lignan- and flavonoid-rich plant foods may contribute to reduction of estrogen-dependent disease, such as breast cancer.

<16>

Authors
Ramanathan R. Das NP. Tan CH.
Institution
Department of Biochemistry, Faculty of Medicine, National University of Singapore.
Title
Effects of gamma-linolenic acid, flavonoids, and vitamins on cytotoxicity and lipid peroxidation.
Source
Free Radical Biology & Medicine. 16(1):43-8, 1994 Jan. Abstract
Gamma linolenic acid (GLA), a polyunsaturated fatty acid, promoted lipid peroxidation in Raji lymphoma suspension cultures, in a dose (10 microM-100 microM) and time-dependent (4 h-48 h) manner. The increase in lipid peroxidation could be correlated to an increase in cytotoxicity. The plant flavonoids (quercetin, luteolin, butein, rutin) and the fat-soluble components (retinol, retinoic acid, alpha-tocopherol) by themselves did not affect lipid peroxidation in Raji cells. Quercetin, luteolin, retinol, and alpha-tocopherol were able to inhibit cell proliferation significantly. Although GLA only decreased the cytotoxicity of retinol-treated cells, the latter compound was able to block the prooxidative action of GLA by scavenging the free radicals induced by it. Quercetin at 50 and 100 microM exerted equipotent superoxide anion scavenging effects, but at the higher concentration it had no effect on lipid peroxidation. Although the bioactive test compounds are well known natural antioxidants, interestingly, our data showed that their potent cytotoxic actions do not involve free radicals or lipid peroxidation reactions.

<17>

Authors
Duarte J. Perez Vizcaino F. Utrilla P. Jimenez J. Tamargo J. Zarzuelo A. Institution
Department of Pharmacology, School of Pharmacy, Universidad de Granada, Spain.
Title
Vasodilatory effects of flavonoids in rat aortic smooth muscle. Structure-activity relationships.
Source
General Pharmacology. 24(4):857-62, 1993 Jul. Abstract

  1. Flavonoids relaxed the contractions induced by noradrenaline, KCl or phorbol 12-myristate, 13-acetate in rat aortic strips, the order of potency being: flavonols (quercetin, kaempferol, pentamethylquercetin) > flavones(luteolin, apigenin) > flavanols((+)-catechin, (-)-epicatechin) which correlates with the reported order of potency to inhibit protein kinase C. 2. The relaxant effects of kaempferol and luteolin were slightly potentiated by isoprenaline and those of pentamethylquercetin, kaempferol and apigenin by sodium nitroprusside. 3. It is concluded that the main vasodilatory mechanism of flavonoids seems to be the inhibition of protein kinase C. Inhibition of cyclic nucleotide phosphodiesterases or decreased Ca2+ uptake may also contribute to their vasodilatory effects.

<18>

Authors
Edenharder R. von Petersdorff I. Rauscher R. Institution
Institute of Hygiene, University of Mainz, Germany. Title
Antimutagenic effects of flavonoids, chalcones and structurally related compounds on the activity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and other heterocyclic amine mutagens from cooked food. Source
Mutation Research. 287(2):261-74, 1993 Jun. Abstract
Sixty-four flavonoids were tested for their antimutagenic potencies with respect to IQ in Salmonella typhimurium TA98 and in part also towards MeIQ, MeIQx, Trp-P-2, and Glu-P-1 and in S. typhimurium TA100. Antimutagenic potencies were quantified by the inhibitory dose for 50% reduction of mutagenic activity (ID50). A carbonyl function at C-4 of the flavane nucleus seems to be essential for antimutagenicity: two flavanols and four anthocyanidines were inactive. Again, five isoflavons, except biochanin A, were inactive. Within the other groups of 21 flavones, 16 flavonols and 16 flavanones the parent compounds flavone, flavonol, and flavanone possessed the highest antimutagenic potencies (ID50: 4.1, 2.5, 5.5 nmoles). Increasing polarity by introduction of hydroxyl functions reduced antimutagenic potency. Reducing polarity of hydroxy flavonoids by methyl etherification, however, increased antimutagenic potency again. 6-Hydroxy- and 2'-hydroxy substituted flavonoids were considerably less potent antimutagens. Of 11 flavonoid glycosides tested all compounds except apigenin- and luteolin-7-glucoside (ID50:74, 115 nmoles) were inactive or only weakly antimutagenic. Rings C and A of the nucleus were not essential for antimutagenicity: chalcone and three derivatives were nearly as active as comparable flavones while antimutagenicity of benzylidenacetone was considerably reduced (ID50: 95 nmoles). Cinnamylaldehyde and cinnamoates, however, were inactive. A planar structure in the vicinity of the carbonyl group may also be important for antimutagenicity. Flavanones were less potent antimutagens than the corresponding flavones, but dihydrochalcones and 14 structurally related saturated aromatic carbonyl compounds were inactive. Fisetin and 6-hydroxyflavone were competitive inhibitors, but luteolin was a mixed type inhibitor. The inhibition mechanisms of flavone, kaempferol, morin, flavanone, and 2'-hydroxyflavanone were concentration dependent, being competitive at low concentrations and mixed or non-competitive (2'-hydroxyflavanone) at concentrations about the ID50 value. No fundamental differences between the two tester strains and no clear influence of mutagen structure on antimutagenic potency could be detected.

<19>

Authors
Chang WC. Hsu FL.
Institution
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China. Title
Inhibition of platelet activation and endothelial cell injury by polyphenolic compounds isolated from Lonicera japonica Thunb. Source
Prostaglandins Leukotrienes & Essential Fatty Acids. 45(4):307-12, 1992 Apr. Abstract
Effects of the polyphenolic compounds isolated from Lonicera japonica Thunb on platelet aggregation, platelet thromboxane biosynthesis and hydrogen peroxide-induced endothelial cell injury were studied. With regard to the inhibitory effect on human platelet aggregation, methyl caffeate, 3,4-di-O-caffeoylquinic acid and methyl 3,4-di-O-caffeoylquinate had a strong effect. They significantly inhibited the second wave of platelet aggregation induced by ADP. Concerning thromboxane biosynthesis triggered by calcium ionophore A23187 in platelets, methyl caffeate and methyl 3,4-di-O-caffeoylquinate had the most potent inhibitory effect. Methyl 3,4-di-O-caffeoylquinate directly inhibited the conversion of arachidonic acid to thromboxane by platelet microsomes, while methyl caffeate did not have any significant effect on thromboxane biosynthesis in platelet microsomes. In the prevention of hydrogen peroxide-induced endothelial cell injury in culture, protocatechuic acid, methyl caffeate, methyl chlorogenic acid and luteolin were significantly effective. The inhibitory effect on platelet activation and the cytoprotective effect on hydrogen peroxide-induced cell injury may explain the possible role of polyphenolic compounds isolated from Lonicera japonica Thunb in maintaining vascular homeostasis.

<20>

Authors
Cholbi MR. Paya M. Alcaraz MJ.
Institution
Departamento de Farmacologia y Farmacotecnia, Facultad de Farmacia, Valencia, Spain.
Title
Inhibitory effects of phenolic compounds on CCl4-induced microsomal lipid peroxidation.
Source
Experientia. 47(2):195-9, 1991 Feb 15. Abstract
The antiperoxidative effects of 35 phenolic compounds, most of them belonging to the flavonoid class, were investigated using CCl4-induced peroxidation of rat liver microsomes. This system was rather insensitive to gallic acid, methyl gallate and ellagic acid. Nevertheless it was inhibited by flavonoids and structure/activity relationships were established. The most potent compounds were gardenin D, luteolin, apigenin (flavones), datiscetin, morin, galangin (flavonols), eriodictyol (flavanone), amentoflavone (biflavone) and the reference compound, (+)-catechin. The natural polymethoxyflavone gardenin D has shown a potency comparable to that of (+)-catechin and higher than that of silybin. Thus, it may be considered as a new type of natural antioxidant with potential therapeutical applications.

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Authors
Robak J. Shridi F. Wolbis M. Krolikowska M. Institution
Department of Pharmacology, Copernicus Academy of Medicine, Krakow, Poland. Title
Screening of the influence of flavonoids on lipoxygenase and cyclooxygenase activity, as well as on nonenzymic lipid oxidation. Source
Polish Journal of Pharmacology & Pharmacy. 40(5):451-8, 1988 Sep-Oct. Abstract
Thirty nine flavonoids, isolated from plants, were tested in respect of their influence on soybean lipoxygenase activity, cyclooxygenase activity and inhibition of ascorbic acid-stimulated malonaldehyde formation in liver lipids. Almost all of the tested compounds were antioxidants and stimulated cyclooxygenase when arachidonic acid was used as a substrate at a concentration of 100 microM. Eleven flavonoids were inhibitors of soybean lipoxygenase. A good correlation between the chemical structure and the tested activity was observed. The most active compounds in all tests were luteolin, 6-hydroxyluteolin, nepetin,
quercetagetin, patuletin and myricetin.

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Authors
Mascolo N. Pinto A. Capasso F.
Institution
Departament of Experimental Pharmacology, University of Naples, Italy. Title
Flavonoids, leucocyte migration and eicosanoids. Source
Journal of Pharmacy & Pharmacology. 40(4):293-5, 1988 Apr. Abstract
Quercetin reduced the concentration of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the pleural exudate induced in rats by 1% carrageenan given intrapleurally. Leucocyte migration in the exudate was also reduced by the flavonoid. Inhibition of eicosanoids and leucocytes in the exudate was dose-related. Quercetin also reduced LTB4 synthesis in cells stimulated with ionophore A23187, either ex-vivo or in-vitro. A similar, though less active, mode of action was found with quercitrin, while apigenin and luteolin reduced leucocyte accumulation and PGE2 formation, but not LTB4-formation.

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Authors
Markaverich BM. Roberts RR. Alejandro MA. Johnson GA. Middleditch BS. Clark JH.
Institution
Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030. Title
Bioflavonoid interaction with rat uterine type II binding sites and cell growth inhibition.
Source
Journal of Steroid Biochemistry. 30(1-6):71-8, 1988. Abstract
Competition analysis with a number of known bioflavonoids demonstrated that these compounds (luteolin, quercetin, pelargonin) compete for [3H]estradiol binding to cytosol and nuclear type II sites in rat uterine preparations. The inhibition of [3H]estradiol binding to type II sites was specific and these bioflavonoids did not interact with the rat uterine estrogen receptor. Since estradiol stimulation of nuclear type II sites in the rat uterus is highly correlated with cellular hypertrophy and hyperplasia, we assessed the effects of these compounds on the growth of MCF-7 human breast cancer cells in culture and on estradiol stimulation of uterine growth in the immature rat. The data demonstrated that addition of quercetin (5-10 micrograms/ml) to MCF-7 cell cultures resulted in a dose-dependent inhibition of cell growth (DNA/flask). This effect was reversible by removal of quercetin from the culture medium, or by the addition of 10 nM estradiol-17 beta to these cell cultures containing this bioflavonoid. Since estradiol-17 beta (10 nM) stimulated nuclear type II sites and proliferation of MCF-7 cells, we believe bioflavonoid inhibition of MCF-7 cell growth may be mediated through an interaction with nuclear type II sites. This hypothesis was confirmed by in vivo studies which demonstrated that injection of luteolin or quercetin blocked estradiol stimulation of nuclear type II sites in the immature rat uterus and this correlated with an inhibition of uterine growth (wet and dry weight). These studies suggest bioflavonoids, through an interaction with type II sites, may be involved in cell growth regulation.

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Authors
Vrijsen R. Everaert L. Boeye A.
Institution
Department of Microbiology and Hygiene, Vrije Universiteit Brussel, Belgium. Title
Antiviral activity of flavones and potentiation by ascorbate. Source
Journal of General Virology. 69 ( Pt 7):1749-51, 1988 Jul. Abstract
We compared the anti-poliovirus activities of three flavones, quercetin, luteolin and 3-methylquercetin, which differ only at ring position 3. 3-Methylquercetin was the most potent compound. Quercetin exhibited antiviral activity only when protected against oxidative degradation by ascorbate. The antiviral activity of luteolin was comparable to that of ascorbate-stabilized quercetin.

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Authors
Nishino H. Nagao M. Fujiki H. Sugimura T. Title
Role of flavonoids in suppressing the enhancement of phospholipid metabolism by tumor promoters.
Source
Cancer Letters. 21(1):1-8, 1983 Nov.
Abstract
Quercetin, a ubiquitous flavonoid in plants, inhibited the incorporation of [32P]inorganic phosphate (32Pi) into phospholipid of HeLa cells enhanced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent tumor promoter. Among the flavonoids tested, luteolin was the most effective in inhibiting the action of TPA. Studies on structure-activity relationships demonstrated that more hydroxylated flavones and flavonols had stronger inhibitory effects. Quercetin and luteolin also inhibited enhancement of 32Pi-incorporation into phospholipid by dihydroteleocidin B, another potent tumor promoter. The inhibitory effect of quercetin on the biological action of tumor promoters is interesting in relation to the non-carcinogenicity of this flavonoid in animals, in spite of its mutagenicity.