X-Message-Number: 11859
Date: Sun, 30 May 1999 14:48:21 -0700 (PDT)
From: Doug Skrecky <>
Subject: example of longevity related medline abstracts -(long!)

To bypass this long article do a find on "message #". This will skip to
the next selection. This is an example of how medline abstracts can fill
up a web site with information quickly and easily. (Note: May be truncated
by cryonet server.)

---------- Forwarded message ----------
Subject: luteolin may increase human lifespan - (long)

Note: The least expensive source of luteolin that the poster is aware of
is rooibos tea leaves. If anyone knows of a potent supplemental source
please point this out. As things stand encapsulating crushed rooibos tea
leaves appears to be the most potent source.

Citations: 1-25
  Takahashi T.  Kobori M.  Shinmoto H.  Tsushida T.
  Iwate Industrial Research Institute, Japan.
  Structure-activity relationships of flavonoids and the induction of
  granulocytic- or monocytic-differentiation in HL60 human myeloid leukemia
  Bioscience, Biotechnology & Biochemistry.  62(11):2199-204, 1998 Nov.
  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.

  Brown JE.  Rice-Evans CA.
  International Antioxidant Research Centre, UMDS-Guy's Hospital, London, UK.
  Luteolin-rich artichoke extract protects low density
  lipoprotein from oxidation in vitro.
  Free Radical Research.  29(3):247-55, 1998 Sep.
  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.

  Shimoi K.  Okada H.  Furugori M.  Goda T.  Takase S.  Suzuki M.  Hara Y. 
  Yamamoto H.  Kinae N.
  School of Food and Nutritional Sciences, University of Shizuoka, Japan.
  Intestinal absorption of luteolin and
  luteolin 7-O-beta-glucoside in rats and humans.
  FEBS Letters.  438(3):220-4, 1998 Nov 6.
  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.

  Noroozi M.  Angerson WJ.  Lean ME.
  Department of Human Nutrition, Glasgow University, Royal Infirmary, United
  Effects of flavonoids and vitamin C on oxidative DNA damage to human
  American Journal of Clinical Nutrition.  67(6):1210-8, 1998 Jun.
  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.

  Wang C.  Kurzer MS.
  Department of Food Science and Nutrition, University of Minnesota, St. Paul
  55108, USA.
  Phytoestrogen concentration determines effects on DNA synthesis in human
  breast cancer cells.
  Nutrition & Cancer.  28(3):236-47, 1997.
  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.

Unique Identifier
  Agullo G.  Gamet-Payrastre L.  Manenti S.  Viala C.  Remesy C.  Chap H. 
  Payrastre B.
  Laboratoire des Maladies Metaboliques, INRA de Theix, Ceyrat, France.
  Relationship between flavonoid structure and inhibition of
  phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein
  kinase C inhibition.
  Biochemical Pharmacology.  53(11):1649-57, 1997 Jun 1.
  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.

  Fotsis T.  Pepper MS.  Aktas E.  Breit S.  Rasku S.  Adlercreutz H.  Wahala
  K.  Montesano R.  Schweigerer L.
  Division of Hematology and Oncology, Children's Hospital, Ruprecht-Karls
  University, Heidelberg, Germany. 
  Flavonoids, dietary-derived inhibitors of cell proliferation and in vitro
  Cancer Research.  57(14):2916-21, 1997 Jul 15.
  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.

  Sadzuka Y.  Sugiyama T.  Shimoi K.  Kinae N.  Hirota S.
  School of Pharmaceutical Sciences, University of Shizuoka, Yada, Japan.
  Protective effect of flavonoids on doxorubicin-induced cardiotoxicity.
  Toxicology Letters.  92(1):1-7, 1997 Jun 16.
  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.

  Edenharder R.  Tang X.
  Department of Hygiene and Environmental Medicine, University of Mainz,
  Inhibition of the mutagenicity of 2-nitrofluorene, 3-nitrofluoranthene and
  1-nitropyrene by flavonoids, coumarins, quinones and other phenolic
  Food & Chemical Toxicology.  35(3-4):357-72, 1997 Mar-Apr.
  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.

  Pettit GR.  Hoard MS.  Doubek DL.  Schmidt JM.  Pettit RK.  Tackett LP. 
  Chapuis JC.
  Cancer Research Institute, Arizona State University, Tempe 85287-1604, USA.
  Antineoplastic agents 338. The cancer cell growth inhibitory. Constituents of
  Terminalia arjuna (Combretaceae).
  Journal of Ethnopharmacology.  53(2):57-63, 1996 Aug.
  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.

  Shimoi K.  Masuda S.  Shen B.  Furugori M.  Kinae N.
  Laboratory of Food Hygiene, School of Food and Nutritional Sciences,
  University of Shizuoka, Japan.
  Radioprotective effects of antioxidative plant flavonoids in mice.
  Mutation Research.  350(1):153-61, 1996 Feb 19.
  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.

  Zarzuelo A.  Jimenez I.  Gamez MJ.  Utrilla P.  Fernadez I.  Torres MI. 
  Osuna I.
  Departamento de Farmacologia, Facultad de Farmacia, Universidad de Granada,
  Effects of luteolin 5-O-beta-rutinoside in
  streptozotocin-induced diabetic rats.
  Life Sciences.  58(25):2311-6, 1996.
  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.

  Shimoi K.  Masuda S.  Furugori M.  Esaki S.  Kinae N.
  Laboratory of Food Hygiene, School of Food and Nutritional Sciences,
  University of Shizuoka, Japan.
  Radioprotective effect of antioxidative flavonoids in gamma-ray irradiated
  Carcinogenesis.  15(11):2669-72, 1994 Nov.
  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.

  Elangovan V.  Sekar N.  Govindasamy S.
  Department of Biochemistry, University of Madras, India.
  Chemopreventive potential of dietary bioflavonoids against
  20-methylcholanthrene-induced tumorigenesis [published erratum appears in
  Cancer Lett 1995 Jan 6;88(1):119-20].
  Cancer Letters.  87(1):107-13, 1994 Nov 25.
  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.

  Wang C.  Makela T.  Hase T.  Adlercreutz H.  Kurzer MS.
  Department of Food Science and Nutrition, University of Minnesota, St Paul
  Lignans and flavonoids inhibit aromatase enzyme in human preadipocytes.
  Journal of Steroid Biochemistry & Molecular Biology.  50(3-4):205-12, 1994
  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.

  Ramanathan R.  Das NP.  Tan CH.
  Department of Biochemistry, Faculty of Medicine, National University of
  Effects of gamma-linolenic acid, flavonoids, and vitamins on cytotoxicity and
  lipid peroxidation.
  Free Radical Biology & Medicine.  16(1):43-8, 1994 Jan.
  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.

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

  Edenharder R.  von Petersdorff I.  Rauscher R.
  Institute of Hygiene, University of Mainz, Germany.
  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.
  Mutation Research.  287(2):261-74, 1993 Jun.
  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

  Chang WC.  Hsu FL.
  Department of Pharmacology, College of Medicine, National Cheng Kung
  University, Tainan, Taiwan, Republic of China.
  Inhibition of platelet activation and endothelial cell injury by polyphenolic
  compounds isolated from Lonicera japonica Thunb.
  Prostaglandins Leukotrienes & Essential Fatty Acids.  45(4):307-12, 1992 Apr.
  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.

  Cholbi MR.  Paya M.  Alcaraz MJ.
  Departamento de Farmacologia y Farmacotecnia, Facultad de Farmacia, Valencia,
  Inhibitory effects of phenolic compounds on CCl4-induced microsomal lipid
  Experientia.  47(2):195-9, 1991 Feb 15.
  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

  Robak J.  Shridi F.  Wolbis M.  Krolikowska M.
  Department of Pharmacology, Copernicus Academy of Medicine, Krakow, Poland.
  Screening of the influence of flavonoids on lipoxygenase and cyclooxygenase
  activity, as well as on nonenzymic lipid oxidation.
  Polish Journal of Pharmacology & Pharmacy.  40(5):451-8, 1988 Sep-Oct.
  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.

  Mascolo N.  Pinto A.  Capasso F.
  Departament of Experimental Pharmacology, University of Naples, Italy.
  Flavonoids, leucocyte migration and eicosanoids.
  Journal of Pharmacy & Pharmacology.  40(4):293-5, 1988 Apr.
  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.

  Markaverich BM.  Roberts RR.  Alejandro MA.  Johnson GA.  Middleditch BS. 
  Clark JH.
  Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030.
  Bioflavonoid interaction with rat uterine type II binding sites and cell
  growth inhibition.
  Journal of Steroid Biochemistry.  30(1-6):71-8, 1988.
  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.

  Vrijsen R.  Everaert L.  Boeye A.
  Department of Microbiology and Hygiene, Vrije Universiteit Brussel, Belgium.
  Antiviral activity of flavones and potentiation by ascorbate.
  Journal of General Virology.  69 ( Pt 7):1749-51, 1988 Jul.
  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.

  Nishino H.  Nagao M.  Fujiki H.  Sugimura T.
  Role of flavonoids in suppressing the enhancement of phospholipid metabolism
  by tumor promoters.
  Cancer Letters.  21(1):1-8, 1983 Nov.
  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

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