BABCOCK UNIVERSITY

COLLEGE OF HEALTH AND MEDICAL SCIENCES

BENJAMIN S. CARSON (SNR) SCHOOL OF MEDICINE

DEPARTMENT OF BIOCHEMISTRY

2014/2015 ORAL SEMINAR PRESENTATION (BCHM 433)

ROLES OF FLAVONOIDS IN HUMAN HEALTHKOLAWOLE, KAYODE DANIEL (11/3269)

BIOCHEMISTRY, 400L

SUPERVISOR: PROFESSOR O.O. ADEBAWO

30TH OCTOBER, 2014.

FLAVONOIDS Flavonoids, formally called vitamin P (are not

really vitamins but possess vitamin-like properties) are phytochemicals or a sub-class of polyphenols that are found to be beneficial to human health.

Due to the variety of pharmacological activities in the mammalian body, flavonoids may also be referred as “nutraceuticals” (Tapas et al., 2008)

Flavonoid Biosynthesis

Figure 2: Schematic representation of flavonoid biosynthesis pathway (Hummer et al., 2008)

Figure 1: Basic structure of flavonoids (Bimlesh et al., 2011)

Sources of FlavonoidsFlavonoids are ubiquitous in photosynthesising cells and are commonly found in • fruits, • vegetables, • nuts, • seeds, • stems, flowers, tea, wine,

propolis and honey (Tim and Andrew, 2005).

Chemical Class` Example Major Dietary Source

Flavonol Quercetin, Rutin, Myricetin,

Kaempferol

Tea, Red wine, Apple,

Tomato, Cherry and Onion

Flavanols Catechin, Gallocatechin Tea and Apple

Flavones Apigenin, Luteolin, Chrysin Thyme and Parsley

Isoflavones Genistein, Glycitein,

Formononetin, Daidzein

Soya bean and other

legumes

Flavanones Hesperidin, Narigenin Grape fruit and Orange

Flavanonols Taxifolin Lemon and sour orange

Table 1: Classification of some flavonoids and their common sources (Mukesh et al., 2005)

Pharmacology of Flavonoids Flavonoids have been reported to exert a wide range of biological activities. These include:• Antioxidant Activity• Cardio-protective effects• Anti-carcinogenic effects• Gastro-protective effects• Treatment of Inflammation• Antimicrobial effects, and many more.

Antioxidant activity Oxidative damage could lead to a lot of degenerative diseases such as artherosclerosis, hypertension, cataracts etc. which occurs when the electron flow generates free radicals, such as O2- centred free radicals, known as reactive oxygen species (ROS), and including superoxide (O2˙¯), peroxyl (ROO˙), alkoxyl (RO˙), hydroxyl (HO˙) and nitric oxide (NO˙) radicals (Hamdoon., 2009).

Indeed, the phenolic groups of flavonoids serve as a source of a readily available ‘‘H” atoms such that the subsequent radicals produced can be delocalized over the flavonoid structure (Tripoli et al., 2007).

Figure 3: Scavenging capacity of free radicals (R.) (Bimlesh et al., 2011)

Figure 4: Formation of peroxy Radical (Bimlesh et al., 2011)

Cardio-Protective Effects

S/N Cardiovascular diseases Influence of Flavonoids

1 Artherosclerosis Decrease in LDL oxidation by LOX inhibition and attenuation of oxidative

stress, inhibition of leucocyte leucocyte adhesion, myeloperoxidase,

decreased expression of iNOS and COX-2.

 

2 Arrhythmia Decrease in oxidative stress.

 

3 Acute Myocardial infarction Decrease in ROS burst, inhibition of platelet aggregation

4 Heart FailureDecrease in oxidative stress (direct ROS scavenging) inhibition of metalloproteinase

 

5 HypertensionVasodilatory properties, inhibition of NADPH oxidase, recovery of NO due to inhibition of superoxide production

 

Table 2: Proposed positive effects of flavonoids on CVS (Bimlesh et al., 2011)

Anti-Carcinogenic Effects Flavonoids are potent bioactive molecules that

possess anti-carcinogenic effects since they can interfere with the initiation, development and progression of cancer by the modulation of cellular proliferation, differentiation, apoptosis, angiogenesis and metastasis (Ramos, 2007).

Some molecular mechanisms of action of flavonoids are given as follows:

• cell cycle arrest (p53 proteins),• tyrosine kinase inhibition,• inhibition of heat shock proteins.

Figure 5: Multistage of carcinogenesis and potential effects of polyphenols on cancer progression (Ramos, 2007)

Gastro-protective Effects The mechanism of action responsible for the anti-

ulcer activity of flavonoids is their antioxidant properties, seen in garcinol, rutin and quercetin.

It involves free radical scavenging, transition metal ions chelation, inhibition of oxidizing enzymes, increase of proteic and nonproteic antioxidants and reduction of lipid peroxidation (Mohamed and Azza, 2011).

Anti-microbial Effects Anti-fungal activity

• A number of moulds and yeasts cause human and animal diseases. For example, species of Aspergillus, Fusarium, and Sporothrix are opportunistic pathogens and easily infect individuals with weak immune systems.• An isoflavone found in a West African legume, alpinum isoflavone, prevents schistosomal infection when applied topically.• Amentoflavone from Selaginella tamariscina (Spikemoss) exhibited potent antifungal activity (IC50 value of 18.3 mg/ml) against several pathogenic fungal strains and has a very low haemolytic effect on human erythrocytes

(Jung et al., 2006).

Anti-Bacterial Effects

• Antibacterial flavonoids having sugar moiety form complexes with proteins by forming either covalent bond, hydrogen bond or hydrophobic effects.

• Their mode of action may be related to their ability to inactivate microbial adhesions, cell envelope transport proteins and others. (Bimlesh et al., 2011).

• Quercetin has been reported to completely inhibit growth of Staphylococcus aureus (Tapas et al., 2008).

Anti-Viral Effects

• The mechanism of antiviral action of polyphenolic compounds is based on their abilities to act as antioxidants, to inhibit enzymes, to disrupt cell membranes, to prevent viral binding and penetration into cells, and to trigger the host cell self-defense mechanisms (Mendel, 2007).

• A recent area of research that is of particular interest is the apparent inhibitory activity of flavonoids (luteolin) against human immunodeficiency virus (HIV) (Andrew and Tim, 2005)

• The HIV-1 transactivator of transcription (Tat) protein engages positive transcription elongation factor b (pTEFb) complex (cycT1 and CDK9), increasing RNA pol II activity and driving viral transcriptional elongation.

• To a large extent, the introduction of combination antiretroviral treatment (cART) has curtailed viral replication below the detection limit (<50 copies/mL) and significantly reduced the devastating impact of HIV-1.

(Mehla et al., 2011)

• These three flavonoids are found to be nontoxic and have anti-HIV-1 activity.

• Luteolin was the most potent and inhibited HIV-1 infection by abrogating Tat-mediated LTR activity.

Figure 6: Inhibition of HIV-1 by flavonoids (Mehla, 2011)

Anti-Inflammatory Effects of Flavonoids Inflammation is a normal biological process in response to

tissue injury, microbial pathogen infection, and chemical irritation.

In general, normal inflammation is rapid and self-limiting, but aberrant resolution and prolonged inflammation cause various chronic disorders (Pan et al., 2010).

Flavonoids are able to inhibit expression of isoforms of inducible nitric oxide synthase, cyclooxygenase, and lipooxygenase, which are responsible for the production of a great amount of nitric oxide, prostanoids, leukotrienes, and other mediators of the inflammatory process such as cytokines, chemokines, or adhesion molecules (Tunon et al., 2009).

Anti-thrombotic Activity of FlavonoidArachidonic acid released by inflammatory

conditions is metabolized by platelets to form prostaglandin, endoperperoxides and thromboxane A2 thus contributing to platelet activation and aggregation.

Platelet aggregation further contributes to atherosclerosis and acute platelet thrombus formation.

The main antiaggregatory effect of flavonoid is by the inhibition of thromboxane A2 formation.

(Bimlesh et al., 2011)

Flavonoid RDA (Recommended Dietary Allowance)

There are no official dosages for bioflavonoids.

Doses in most supplements sold range from 30 to 200 milligrams a day which is acceptable for general maintenance.

Clinical trials tend to be based on much higher doses of between 500 to 2000 mg (milligrams). For therapeutic purposes the range can be between 50 to 500 mg per day.

(Health Supplements Nutritional Guide, 2009)

Toxicological Profile of FlavonoidsWith the exception of green tea, research on flavonoids in

general shows no known toxic effects.  High doses do not appear to cause serious side effects, even for amounts as high as 100 grams a day.  Excess intake is simply excreted in urine.

The main symptom of flavonoid overdose is diarrhea.

As for green tea, highly concentrated doses of it might contain too much caffeine for cancer and hepatitis patients, and for those people sensitive to caffeine.

(Health Supplements Nutritional Guide, 2009)

ConclusionStructure function relationship of flavonoids is

epitome of major biological activities.

Medicinal efficacy of many flavonoids as antibacterial, hepatoprotective, anti-inflammatory, anticancer, and antiviral agents is well established.

Therapeutic use of new compounds must be validated using specific biochemical tests.

Further achievements will provide newer insights and will certainly lead to a new era of flavonoid based pharmaceutical agents for the treatment of many infectious and degenerative diseases.

Remember:“DOSAGE DETERMINES TOXICITY”

THANK YOU FOR

LISTENING

References• Bimlesh K., Prashant T., Manoj S., Pardeep S., and Harleen S.

(2011). A Review of Phytochemistry and pharmacology of Flavonoids. Internationale Pharmaceutica Scientia, 1 (1): 25- 38.

• Hamdoon A.M. (2009). Natural and synthetic flavonoid derivatives with potential Antioxidant and Anticancer Activities. published thesis, 16.

• Http://WWW.HealthSupplementNutritionalGuide.Org. Retrieved 28th september, 2014.

• Jung, H.J., Sung, W.S., Yeo, H.S., Kim H.S., Lee, I.S., Woo, E.R., and Lee D.G. (2006). Arch. Pharm. Research. 29:746.

• Mehla, R., Bivalkar-Mehla, S., Chauhan, A. (2011). A Flavonoid, Luteolin, Cripples HIV-1 by Abrogation of Tat Function. PLoS ONE 6(11): e27915. doi:10.1371/journal.pone.0027915

• Mendel, Friedman (2007). Overview of antibacterial, antitoxin, antiviral, and antifungal activities of tea flavonoids and teas. Mol. Nutr. Food Res., 51: 116-134.

• Mohamed, Morsy and Azza, El-Sheikh, (2011). Prevention of gastric ulcers, peptic ulcer disease,Dr.Jianyuan Chai (Ed), 456 Pp; ISBN: 978-953-307-976-9, Intech, DOI: 10.5772/17942.

• Mukesh Nandave, S. Ojha, D. Arya (2005). Protective role of flavonoids in cardiovascular diseases. Natural Product Radiance, 4(3): 166- 176.

• Pan M., S. Lai, and C. Ho (2010). Anti-inflammatory activity of natural dietary flavonoids, Food and Function, 1(1): 15–31.

• Ramos, S. (2007). Effects of dietary flavonoids on apoptic pathways related to cancer chemoprevention. Journal of Nutritional Biochemistry, 18: 427-442.

• Tapas, A.R., Sakarkarl,D.M., and Kakde, R.B. (2008). Flavonoids as Nutraceuticals: A Review. Tropical Journal of Pharmaceutical Research, 7(3): 1089–1099.

• Tim-Cushnie T.P, and Andrew J. (2005). Antimicrobial activity of flavonoids. International Journal of Antimicrobial Agents, 26: 343-356.

• Tunon, M., M. Garcia-Mediavilla, S. Sanchez-Campos, and J. Gonzalez-Gallego (2009). “Potential of flavonoids as antiinflammatory agents: modulation of pro-inflammatory gene expression and signal transduction pathways. Current Drug Metabolism, 10(3): 256–271.