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Text of The Biochemistry and Medical Significance of the Flavonoids 2002

Pharmacology & Therapeutics 96 (2002) 67 202

The biochemistry and medical significance of the flavonoidsBent H. Havsteen*Department of Biochemistry, University of Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany

Abstract Flavonoids are plant pigments that are synthesised from phenylalanine, generally display marvelous colors known from flower petals, mostly emit brilliant fluorescence when they are excited by UV light, and are ubiquitous to green plant cells. The flavonoids are used by botanists for taxonomical classification. They regulate plant growth by inhibition of the exocytosis of the auxin indolyl acetic acid, as well as by induction of gene expression, and they influence other biological cells in numerous ways. Flavonoids inhibit or kill many bacterial strains, inhibit important viral enzymes, such as reverse transcriptase and protease, and destroy some pathogenic protozoans. Yet, their toxicity to animal cells is low. Flavonoids are major functional components of many herbal and insect preparations for medical use, e.g., propolis (bees glue) and honey, which have been used since ancient times. The daily intake of flavonoids with normal food, especially fruit and vegetables, is 1 2 g. Modern authorised physicians are increasing their use of pure flavonoids to treat many important common diseases, due to their proven ability to inhibit specific enzymes, to simulate some hormones and neurotransmitters, and to scavenge free radicals. D 2002 Elsevier Science Inc. All rights reserved.Keywords: Flavonoids; Benzopyrones; Heat shock proteins; Gene expression; Enzyme inhibition Abbreviations: Ab, b-amyloid; AC, adenylate cyclase; ACTH, adrenocorticotrophic hormone; AD, Alzheimers disease; AIDS, acquired immunodeficiency syndrome; APC, antigen-presenting cell; cAMP, cyclic AMP; CAT, chloramphenicol acetyltransferase; cGMP, cyclic GMP; CoA, coenzyme A; COX, cyclooxygenase; CSF, colony stimulating factor; DAG, diacylglycerol; ER, estrogen receptor; FA, fatty acid; GABA, g-aminobutyric acid; GC-MS, gas chromatography-mass spectrometry; GSH, glutathione; HIV, human immunodeficiency virus; HMG, 3-hydroxy-3-methyl-glutaryl; HSE, heat shock regulatory element; HSF, heat shock factor; HSP, heat shock protein; HTLV, human T-lymphocyte-associated virus; IAA, indolyl acetic acid; ICE, interconverting enzyme; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LDL, low-density lipoprotein; MHC, major histocompatibility complex; NK-T-Ly, natural killer T-lymphocyte; NO, nitric oxide; PDE, phosphodiesterase; PG, prostaglandin; PGI2, prostacyclin; PIL, phosphatidylinositol lipase; PKC, protein kinase C; PL, phospholipase; PRR, proton relaxation rate; Pyr-P, pyridoxal phosphate; R, receptor; RA, rheumatoid arthritis; SIV, Simian immunodeficiency virus; SOD, superoxide dismutase; THF, tetrahydrofolate; TIMP, tissue inhibitor of matrix metalloproteinase; TNF, tumor necrosis factor; Tx, thromboxane; XO, xanthine oxidase.

Contents 1. 2. 3. Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . The chemistry of flavonoids . . . . . . . . . . . . . . . . . . . 3.1. Structure and nomenclature. . . . . . . . . . . . . . . . 3.2. The oxidation-reduction potential of flavonoids . . . . . 3.3. Acid-base properties . . . . . . . . . . . . . . . . . . . 3.3.1. The tautomery of anthocyanin . . . . . . . . . . 3.4. Absorption and fluorescence spectra of flavonoids . . . . 3.5. Optical activity of flavonoids. . . . . . . . . . . . . . . 3.6. Radical scavenging by flavonoids . . . . . . . . . . . . 3.7. Linear free-energy relationships applied to the flavonoids 3.7.1. The nature of the problem . . . . . . . . . . . . 3.7.2. Linear free-energy relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 70 71 71 71 72 72 74 76 77 80 80 80

* Current Address: Abildgaardsvej 49, DK-2830 Virum, Denmark. Tel.: +49-0431-880-3214. E-mail address: [email protected] (B.H. Havsteen). 0163-7258/02/$ see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 1 6 3 - 7 2 5 8 ( 0 2 ) 0 0 2 9 8 - X

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4. 5.

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7. 8.

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10. 11. 12.

13. 14. 15.

16. 17.

The occurrence of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Distribution in nature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Identification of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Magnetic resonance spectrometry of flavonoids . . . . . . . . . . . . . . . . . . . 5.1.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Information available from proton relaxation rates . . . . . . . . . . . . . 5.1.3. The theory of pulsed nuclear magnetic resonance . . . . . . . . . . . . . . 5.1.4. The measurement of relaxation times . . . . . . . . . . . . . . . . . . . . 5.1.5. Applications of proton resonance relaxation. . . . . . . . . . . . . . . . . 5.1.6. Concluding remarks on nuclear magnetic resonance . . . . . . . . . . . . 5.2. Identification of flavonoids by gas chromatography-mass spectrometry . . . . . . . 5.2.1. Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2. Analysis of propolis by gas chromatography-mass spectrometry . . . . . . 5.3. Analysis of propolis by high performance liquid chromatography . . . . . . . . . . 5.3.1. Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2. The analytical procedure. . . . . . . . . . . . . . . . . . . . . . . . . . . The biosynthesis of flavonoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Anabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. The genetics of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The role of the flavonoids in plant physiology . . . . . . . . . . . . . . . . . . . . . . . 7.1. Flavonoids as signals of symbiosis . . . . . . . . . . . . . . . . . . . . . . . . . . The pharmacology of flavonoids in animals . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Acute toxicity of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Long-term effects of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. The catabolism of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The immunology of the flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. The flavonoids as antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Flavonoids as immune modulators . . . . . . . . . . . . . . . . . . . . . . . . . . Scavenging of free radicals by flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . The electron transfer catalysis by flavonoids . . . . . . . . . . . . . . . . . . . . . . . . The flavonoids as enzyme inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1. Hydrolases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2. Oxidoreductases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3. Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.4. Isomerases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.5. Transferases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.6. Ligases and lyases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The hormone action of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The mutagenic potential of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . The influence of the flavonoids on the sensory system . . . . . . . . . . . . . . . . . . . 15.1. The olfactory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2. The neurostimulatory effect of flavonoids . . . . . . . . . . . . . . . . . . . . . 15.3. The analgesic effect of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . Complexes of flavonoids with heavy metal ions. . . . . . . . . . . . . . . . . . . . . . . Medical, technical, gastronomic, and other applications of flavonoids . . . . . . . . . . . 17.1. Hypertension and microbleeding . . . . . . . . . . . . . . . . . . . . . . . . . . 17.2. Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.3. The effect of flavonoids on the condition of diabetes mellitus patients . . . . . . . 17.4. Local anaesthesia by flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . 17.5. Protein-rich oedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.6. Loosening of connective tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.7. The effect of flavonoids on allergy and asthma. . . . . . . . . . . . . . . . . . . 17.8. The influence of flavonoids on cancer . . . . . . . . . . . . . . . . . . . . . . . 17.8.1. The biology of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 17.8.2. The treatment of cancer by flavonoids . . . . . . . . . . . . . . . . . . 17.8.3. Biochemical processes of cancer influenced by flavonoids . . . . . . . 17.8.4. Stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.9. The influence of flavonoids on cardiovascular diseases. . . . . . . . . . . . . . . 17.9.1. The genetic disposition. . . . . . . . . . . . . . . . . . . . . . . . . . 17.9.2. The role of flavonoids in the dietary component of cardiovascular stress

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17.9.3. Flavonoids in the management of ischaemia/reperfusion damage . . . . . . The effect of flavonoids on gastrointestinal ulcers . . . . . . . . . . . . . . . . . . . The effect of flavonoids on rheumatic diseases . . . . . . . . . . . . . . . . . . . . . Bacterial infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The antiviral properties of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . Morbus alzheimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.15.1. Cellular reactions to damage . . . . . . . . . . . . . . . . . . . . . . . . 17.15.2. Peroxidation of lipids by free radicals . . . . . . . . . . . . . . . . . . . 17.15.3. Metabolic changes caused by organic solvents . . . . . . . . . . . . . . . 17.15.4. Hypoxic cell damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.15.5. Tissue regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.15.6. The anabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.16. Heavy metal detoxification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.17. Hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.17.1. Treatment of hypercholesterolemia . . . . . . . . . . . . . . . . . . . . . 17.17.2. Sites of flavonoid action in cholesterol metabolism. . . . . . . . . . . . . 17.18. Stimulation of the immune system by flavonoids. . . . . . . . . . . . . . . . . . . . 17.19. The potential of flavonoids in the acquired immunodeficiency syndrome prophylaxis and therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.19.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.19.2. The origin of the acquired immunodeficiency syndrome . . . . . . . . . . 17.19.3. The human immunodeficiency virus gene . . . . . . . . . . . . . . . . . 17.19.4. Possible targets of antiviral drugs . . . . . . . . . . . . . . . . . . . . . . 17.20. The use of flavonoids in birth control (fertility control) . . . . . . . . . . . . . . . . 18. Interaction of flavonoids with other drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19. Prospects of further applications of flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.10. 17.11. 17.12. 17.13. 17.14. 17.15.

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1. Preface Humans have gathered food and medical herbs ever since their arrival on earth. We were guided then by instinct, followed by experience, and more recently, also by rational thought. For millions of years, mankind has fared quite well using this approach, but after the development of science and technology, many people felt that the current state of affairs was quite satisfactory and, hence, they failed to support research and education adequately. Yet, the activities of humans on this clod evidently interact effectively with other evolving systems of nature, with consequences that may become very harmful to higher life soon. Therefore, it is time to examine more closely what we are eating, how diseases can be treated more rationally, and how we can more effectively conserve our natural resources. Although the analyses of such problems at the moment are neither sufficiently diversified nor adequately penetrant, the feeling that such work is urgent has become widespread (Geissman, 1963; Harborne, 1988a, 1988b; Harnaj, 1975; Dixon et al., 1998; Montanari et al., 1998); many living species of all biological kingdoms become extinct before their significance to the ecology has been ascertained. Reasons for this are based on the laws of nature and the increasingly aggressive and thoughtless exploitation of nature by humans. One of our natural resources is the plants in remote forests, some of

which undoubtedly contain compounds of potential med...