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LutiMax - A Natural Bioflavonoid Product Containing Luteolin

GENERAL
  • Luteolin (3´,4´,5,7-tetrahydroxyflavone) is a flavonoid widely distributed in the plant kingdom. It was isolated e.g. from Reseda luteola L.1, Achillea millefolium L.2, Chamomillae requtita2,3, Cynara scolymus4, Thymus vulgaris, Limonium sinuatum5, Vitex rotundifolia6, Erigeron canadensis L.7,8, Sophora angustifolia9, Satureja obovata10, Lonicera japonica11,12. It was also found in Propolis, the bee glue.

  • Chemically, Luteolin is a yellow microcrystalline powder. It is sparingly soluble in water, but soluble in alkali.
PHYSIOLOGICAL BENEFITS

Among possible therapeutic applications of oral luteolin are allergies, chronic inflammatory conditions (respiratory, gastrointestinal, musculoskeletal, etc) atherosclerosis and other vascular disorders, neoplastic disorders, diabetes and obesity. Externally luteolin can be used for skin allergic/inflammatory disorders and for skin cancer prevention. Luteolin is a promising agent for use in ophthalmology: for prevention and treatment of cataract and of vascular eye disorders.

Luteolin-containing herbal extracts have been used for a long time as traditional herbal remedies:
  • Extracts from Chamomillae requtita (chamomile) and Achillea millefolium L. (yarrow), are rich in Luteolin and its 7-O-glycosides. They are well established in traditional medicine for a wide range of beneficial effects such as antiphlogistic, spasmolytic, analgesic and also moderate antihistamine properties.

  • Extracts from Cynara scolymus, leaves of artichokes, are known for such properties as carminative (facilitating the eructation of gas from the stomach), spasmolytic and anti-emetic (reducing nausea). The dyspeptic syndrome, chronic gastrointestinal and metabolic diseases are traditional indications. Extracts from artichoke also show hepatoprotective properties, strong antioxidative effects and reduce the cholesterol biosynthesis. This can be beneficial in artherosclerosis.

  • Thymus vulgaris, (thyme) extracts are used for spasmolytic and cough-relieving effects on bronchial diseases.

  • Vitex rotundifolia, an evergreen shrub common to Eastern Asia, is used in Chinese medicine for the treatment of inflammation, headache and neuralgia.

  • Propolis, the bee glue, is also rich in Luteolin and its 7-O-glycosides. It is traditionally used in ointments and creams for the treatment of a variety of ulcers and eczemas.
Antioxidant Activity
  • Luteolin, constituent of artichoke leaf extract, showed a concentration-dependent inhibitory activity in several models of oxidative stress.13

  • The antioxidant potential of Luteolin, measured in Trolox test, is twice stronger than that of vitamin E14,15. Luteolin is a significantly more potent antioxidant than the synthetic antioxidant butylated hydroxytoluene (BHT), which is generally used in oxygen sensitive processes16.

  • Luteolin has strong scavenging properties for superoxide radicals20,17.

  • Luteolin is a potent physical quencher of singlet oxygen18. Luteolin inhibits single strand break in DNA induced by singlet oxygen in a dose-dependent manner. Chromosomal aberrations are probably one of the causative incidents in the formation of cancer.
Via enzymatic process:
  • Xanthine oxidase is considered to be the most prominent biological source of harmful superoxide radicals19. Luteolin is a strong competitive inhibitor of xanthine oxidase20, , 19 17, which results in a reduced formation of H2O2. Some recent results showed an IC50 of 7,83 M.21
Lipid Peroxidation

Lipid peroxidation leads to the oxidation of polyunsaturated fatty acids and subsequently to the formation of harmful compounds which are involved in the etiology of many diseases.
  • Luteolin inhibits enzymatic and nonenzymatic-induced lipid peroxidation in rat liver homogenate22,23.

  • Luteolin shows strong antioxidant activities in vitro. Luteolin inhibited lipid peroxidation induced by FeCl2 in rat liver (IC50 = 2,64 g/ml). The effect was dose-dependent.

  • The inhibiting effect of several flavonoids on CCl4-induced lipid peroxidation of rat liver microsomes was studied. Luteolin was among the most effective24.´
Cardiovascular Activity

Luteolin affects the pathogenesis of atherosclerosis by several mechanisms: inhibiting cholesterol biosynthesis at different levels, increasing elimination of cholesterol from liver and inhibiting LDL oxidation.
  • Luteolin causes an inhibition of cholesterol biosynthesis up to 60 % at EC50 values of 30µM.4,25

  • Luteolin showed the ability to increase coronary flow and relaxation velocity in perfused isolated guinea pig hearts26.

  • Luteolin and also Luteolin-4´-O-glycoside decreased the incidence and the importance of hyperkinetic ventricular and reperfusion arrhythmias.27

  • Pretreatment of guinea pigs with Luteolin reduced significantly the ischaemic area by 43 % in experimental cardiac infarction.

  • Luteolin has moderate effects on blood coagulation in vitro.28

  • Experiments in cats and dogs showed that luteolin had significant effects on reducing blood pressure.29
Due to vasodilatory properties:
  • Luteolin exhibits important vasorelaxant behavior. This was demonstrated on smooth muscle cells of rat aorta and rabbit thoracic aorta.10,30 Vasorelaxation or inhibition of contraction is mediated by the influx or release of Ca2+; the mechanism of vasodilatory action of luteolin apparently involves inhibition of protein kinase C and possibly the inhibition of cyclic nucleotide phosphodiesterase.31,32
Due to antiinflammatory properties:
  • Luteolin inhibits platelet aggregation, platelet thromboxane synthesis. It protects against endothelial injury induced by hydrogen peroxide and linoleic acid hydroperoxide (LOOH). Synergistic action with alpha-tocopherol against LOOHinduced cell damage is reported.33,34
Cancer Prevention and Treatment (anticarcinogenic, antimutagenic, antiangiogenic properties)

Luteolin in the low micromolar range inhibits the proliferation of normal and tumor cells, as well as in vitro angiogenesis. Inhibition of extensive neovascularization can contribute to prevention of certain chronic diseases, including solid malignancies.

Luteolin shows strong antiproliferative activity against different human cancer cell lines (in some hormone-dependent cancer lines such as breast, prostate, and thyroid cancer for instance).35, 36, 37, 38, 39
  • Luteolin inhibits tyrosine kinase, an enzyme involved in tumor cell proliferation. By modulating the activity of enzymes, toxicity and carcinogenicity of various xenobiotics may be affected.40

  • Luteolin is an important dietary cancer preventive agent.20, 41, 42 Several studies demonstrated that the addition of Luteolin to the diet of rats inhibits the clastogenicity of salted, sun-dried, broiled and deep-fried food.43

  • Luteolin has strong chemopreventive activity by reducing the formation of carcinogens in food such as heterocyclic amines, polycyclic aromatic hydrocarbons and N-nitroso compounds from precursors. Luteolin is able to block the activation of carcinogens, increase the detoxification of carcinogens and stimulate the errorfree DNA repair.

  • 20-Methylcholanthrene is a strong mutagen that induces fibrosarcoma in 100% of mice fed with it. Dietary supplementation with Luteolin along with 20- methylcholanthrene showed a significant reduction on tumor expression to 60 %. The tumor growth and tumor volume decreased to 85 % compared with the control at the end of the experimental period.44

  • Luteolin has potential anticarcinogenic effects against estrogen-induced mammary carcinogenesis.45,46
The ability of luteolin to inhibit N-acetlytransferase (see section antibacterial) is relevant also for its antineoplastic properties. Luteolin inhibited the arylamine Nacetyltransferase activity and DNA-2-aminofluorene adduct formation in human and mouse leukemia cells for 24h.47

Luteolin displays potent antimutagenic action against some dietary carcinogens (e.g. polychlorinated biphenyl).48

Anti-inflammatory Activity

Luteolin is a component of herbs with anti-inflammatory action and has itself demonstrated effectiveness against inflammatory processes. Inflammation responses are involved in the pathogenesis of atherosclerosis, rheumatoid arthritis, diabetic neuropathy and many other diseases.
  • Luteolin decreases the formation of PAF due to the inhibition of lysoPAF acetyltransferase12 (IC50= 45mM). (Platelet Activating Factor; PAF is a strong mediator involved in inflammation, anaphylactic reaction, etc). Luteolin is a strong non-specific inhibitor of platelet aggregation in rabbit aorta induced by arachidonic acid.30,49

  • It has been reported that anti-inflammatory properties of luteolin are related to its lipooxygenase inhibition activity. Reportedly, inhibition of both 12-lipoxygenase (12-LO) and 5-lipoxygenase (5-LO) are involved The inhibitory effects of flavonoids on arachidonate 12-lipoxygenase and 5-lipoxygenase were investigated. Luteolin was one of the most active compounds with IC50 = 20nM and 102nM, respectively in rat platelets and polymorphonuclear leukocytes.50

  • Chen et al. demonstrated anti-inflammatory activity of luteolin in various animal models, such as inflammations induced by xylene, carrageenin, AcOH, croton oil, and some immunological agonists.51 Luteolin also inhibited acute hypersensitivity in the ileum. Recently anti-inflammatory activity of luteolin was shown in oxazolone- and TPA-induced ear edema in mice.52 Luteolin apparently inhibited the sensitization step, selectively inhibiting IgE.

  • Tordera et al. studied the effects of luteolin on degranulation and arachidonic acid release in rat neutrophils.53 The authors assessed the effects of 24 flavonoid derivatives, reported as anti-inflammatory, on lysosomal enzyme secretion and arachidonic acid release. Luteolin (along with apigenin, fisetin, kaempferol, and quercetin) was among the most potent inhibitors of beta-glucuronidase and lysozyme release. A correlation between degranulation and arachidonic acid release was found.

  • Due to its skin-penetrating ability Luteolin was suggested for topical use as antiphlogistic agent.54

  • The efficacy of Luteolin was demonstrated against acetic acid-induced acute pleurisy (inflammation of the pleura membrane that lines the chest and contains the lung), in rats with results showing a significant reduction in pleural exudate volume with no obvious changes in total exudate leukocyte number.55

  • Luteolin suppressed nitric oxide production possibly through reduction of inducible nitric oxide synthase (iNOS) enzyme expression56. (Nitric oxide is produced by iNOS and is a mediator of inflammation.)
Antidiabetic Activity and Applications Related to Its Complications

Hypoglycemic action:
  • Luteolin inhibits alpha-glucosidase and alpha-amylase.57 Luteolin inhibited alphaglucosidase by 36% at the concentration of 0.5 mg/ml, suggesting that it can suppress postprandial hyperglycemia in patients with non-insulin dependent diabetes mellitus. The glucosidase inhibitory potency of luteolin was stronger than that of acarbose (=glucobay), the widely prescribed antidiabetic drug. (Alphaglucosidase inhibitors are antihyperglycemic agents that inhibit the digestion and absorption of complex carbohydrates, reducing the rise in postprandial blood glucose). Luteolin also inhibited alpha-amylase effectively, although it was less potent than acarbose.
Prevention of diabetes complication:

The impaired glycemic control in diabetes leads to oxidative stress, and numerous micro- and neurovascular abnormalities, including disturbances in microcirculation, capillary hypoxia, and ischemic syndrome. They are of relevance for major diabetic complications, such as: nephropathy (renal disease, and eventually, kidney failure), eye disease (cataract or diabetic retinopathy), neuropathy (different types of nerve damage), and vasculopathy (atherosclerotic coronary and peripheral vascular disease). Due to their antioxidative, antiinflammatory, vasoprotective etc. actions luteolin and its glycosides can be considered for the prevention and treatment of diabetes-related tissue injuries.
  • Inflammatory responses are involved in the pathogenesis of diabetic neuropathy and other diabetic complications. Luteolin is an efficient anti-inflammatory and anti-allergic compound.58 It protects against endothelial injury induced by hydrogen peroxide and linoleic acid hydroperoxide. Luteolin and its glycosides inhibit platelet aggregation and platelet thromboxane synthesis. Luteolin and its glycosides strengthen capillary wall and reduce capillary permeability.59 Strong antioxidative properties of luteolin are well established in many different settings.

  • Anticataract action:

    It has been proven that Luteolin and also Luteolin-7-O-ß-glucopyranoside are among the active principles of Chinese crude drugs used in the treatment of diabetic cataract, keratopathy and nephropathy60, 61. Luteolin isolated from flowers of Buddleja officinalis inhibited in vitro lens aldose reductase, an enzyme involved in the complications of diabetes (IC50=0.21 mcM).

  • Anti-obesity:

    The ability of luteolin to inhibit enzymes involved in the digestion and absorption of carbohydrates can be employed in nutritionnal supplements for weight control. (see paragraph on hypoglycemic action)
Antiallergy Activity

(Stabilization of mast cells (mast cells are important target in allergy processes); inhibition of histamine release, of cytokine production, PAF production, etc.)
  • Flavone Luteolin is considered as one of the most active anti-inflammatory and anti-allergic compounds among bioflavonoids. Particularly it has been shown to inhibit immunoglobulin (IG)E-mediated histamine release from human cultured mast cells, human basophils, murine mast cells. 62 Evidence indicates that luteolin is a potent inhibitor of human mast cell activation through the inhibition of Ca2+ influx and protein kinase C activation.63

  • Luteolin inhibits the production of platelet-activating factor (PAF) in rat peripheral white blood cells at IC50=45M.(PAF is a strong mediator involved in inflammation, anaphylactic reaction etc. Luteolin inhibits acetyl-CoA:1-alkyl-2-lyso-snglycero-3-phosphocholine (lyso PAF) acetyltransferase activity; this inhibition is considered specific, since luteolin does not suppress the activity of cholineacetyltransferase.

  • Anti-allergic properties of luteolin were demonstrated in various models. Cheong et al. studied hexosaminidase release from RBL-2H3 (rat basophilic leukemia mucosal-type mastocytoma line) cells. The authors compared properties of 22 flavonoids and found that luteolin was one of the most effective (with IC50 value for degranulation less than 10 mM). Earlier Kawasaki et al. used the same model to screen 40 flavonoids for inhibitory activity on antigen-induced histamine release from IgE-sensitized RBL-2H3 cells. Luteolin inhibited histamine and LTB4 release from rat peritoneal mast cells;64 histamine release from bovine mast cells, from rat peritoneal mast cells.65 Shen demonstrated that luteolin inhibited release of histamine and of SRS-A (slow-reacting substance of anaphylaxis) from ovalbumin-sensitized lungs of guinea pigs.66

  • Park et al. identified luteolin as the dose-dependent IL-5 inhibitor. Interleukin (IL)-5 is a chemotactic factor that promotes the growth and survival of eosinophils, and plays an important role in the eosinophilia-associated allergic inflammation. Luteolin and several related flavonoid compounds were isolated from Kummerowia striata Thurn. (Leguminosae). The inhibitory potency on IL-5 bioactivity was in the following order: luteolin 4'-O-glucopyranoside (IC50=3.7mM)> apigenin (16.4 m M) » luteolin (IC50=18.7 m M) > (30.0 mM).67
Antiviral Activity

Viral diseases are a major public health concern given the lack of effective methods of treatment. Luteolin has demonstrated anti-viral activity.
  • Luteolin demonstrated the ability to inhibit herpes simplex virus (HSV-1).68

  • Luteolin exhibits anti-poliovirus activity.69

  • Luteolin shows moderate inhibitory effects on avian myeloblastosis virus reverse transcriptase.70
Antibacterial Activity
  • Luteolin has bacteriostatic properties against Staphylococcus aureus.71

  • Luteolin inhibits the growth of Helicobacter pylori, likely by the inhibition of arylamine N-acetyltransferase. The same mechanism apparently is involved in the inhibition of Neisseiria gonorrhoeae. Luteolin dose-dependently inhibited growth of the N. gonorrhoeae cultures for at least 4 hours.72
Gastrointestinal Disturbances
  • Luteolin has antiinflammatory and anti spasmodic actions.73

  • It has been demonstrated that luteolin can dose-dependently inhibit the growth of Helicobacter pylori, which is associated with gastritis, gastric and duodenal ulcers, and possibly gastric cancers. It is suggested that luteolin acts as an uncompetitive inhibitor of arylamine N-acetyltransferase in H.pylori.74,75

  • Chamomile tea, rich in Luteolin, is traditionally used for the treatment of stomach and intestinal complaints76. It has been demonstrated that Luteolin and other flavonoids exert a spasmolytic activity on isolated guinea pig ileum.
Radioprotective Activity

Luteolin may protect from damage induced by ionizing radiation.
  • Luteolin shows a radioprotective effect against micronuclei induction in y-ray irradiated mice. It reduces the frequency of micronucleated reticulocytes in mice after exposure to in y-ray77.
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