Elsevier

Pharmacology & Therapeutics

Volume 96, Issues 2–3, November–December 2002, Pages 67-202
Pharmacology & Therapeutics

The biochemistry and medical significance of the flavonoids

https://doi.org/10.1016/S0163-7258(02)00298-XGet rights and content

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 (bee's 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.

Section snippets

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

Structure and nomenclature

The term flavonoids is a collective noun for plant pigments, mostly derived from benzo-γ-pyrone, which is synonymous with chromone Hassig et al., 1999, Harborne, 1964, Harborne, 1967, Croft, 1998 (Fig. 1).

The group comprises anthocyanidines, hydroxyl-4-dihydroflavonoles; anthocyanides, glycosides of anthocyanidines (Fig. 2); flavonoles, 2-phenyl-3-hydroxy-chromones (Fig. 3); iso-flavonoles, 3-phenyl-2-hydroxy-chromones (Fig. 4); flavones, 2-phenyl-chromones (Fig. 5); iso-flavones,

Distribution in nature

The flavonoids are qualitatively and quantitatively one of the largest groups of natural products known. Since almost all flavonoids are pigments, their colors are undoubtedly associated with some of their important biological functions. The ubiquity of the flavonoids to all geographical zones of herbal growth supports this argument. Since all colors of the spectrum, including its UV region, are represented in the spectra of the flavonoids, their electronic properties appear to include not only

Identification of flavonoids

The complete analysis of the absolute structure and configuration of a flavonoid is usually a complicated task, which requires the application of advanced techniques, e.g., [1H]- and [13C]-NMR-spectrometry, [1H-1H]-correlated spectroscopy, circular dichroism, optical rotatory dispersion, mass spectrometry, and X-ray diffraction. Since only a few laboratories are equipped and staffed to make all of these expensive methods available, simpler approaches to the characterisation of flavonoids are

Anabolism

All green plant cells are capable of synthesizing flavonoids. The biosynthesis invariably begins with the ubiquitous amino acid phenylalanine. It takes different, but related, courses, depending on the kind of flavonoid that is required (Czihay et al., 1976).

At first, the amino group is removed by transamination or oxidative desamination, which produces phenylpyruvate, whereas the amino group is transferred to a keto acid of the citric acid cycle or liberated as an ammonium ion. Two molecules

The role of the flavonoids in plant physiology

The flavonoids are essential constituents of the cells of all higher plants. They resemble in their regulatory properties most of the lipid-soluble vitamins, but serve in addition, due to their color and odor, as communicators with the environment Middleton & Teramura, 1993, Harborne et al., 1976, Brouillard & Cheminat, 1988, Harborne, 1986, Harborne, 1988a, Harborne, 1988b. They are recognised by pollinators, e.g., insects, birds, and animals, which contribute to the dispersion of seeds. The

The pharmacology of flavonoids in animals

So far, the science of pharmacology has concentrated its efforts mainly on potent plant toxins that accidentally may be ingested, if not given or taken with the intention to kill, and on drugs that are being considered for a medical application. In contrast, natural products, which are regularly ingested in high amounts as components of a normal human diet, but which are only slightly toxic, have almost been ignored Hughes & Wilson, 1977, Gábor, 1981. The flavonoids belong to the latter

The immunology of the flavonoids

Small organic compounds such as the flavonoid aglycones are only antigenic if they are bound to macromolecules in the blood, i.e., to plasma proteins. Although immune reactions rarely are problems by the consumption or therapeutic application of flavonoids, they do occur occasionally. At least some flavonoids, therefore, are capable of binding to one or more of the plasma proteins, probably primarily to serum albumin and lipoproteins, since flavonoids are hydrophobic and are transported in bile

Scavenging of free radicals by flavonoids

One of the more prominent properties of the flavonoids is their excellent radical scavenging ability. It is also a valuable aspect for therapeutic and prophylactic applications of flavonoids, e.g., after infection, inflammation, burns, or radiation injury Fritz-Niggli & Frohlich, 1980, Fritz-Niggli & Rao, 1978, Fritz-Niggli, 1968, Panthong et al., 1989, Hladon et al., 1980, Gabor, 1972a, Gabor, 1972b, Schmidt et al., 1980, Wozniak & Braun, 1972, Casley-Smith & Bolton, 1973, Casley-Smith et al.,

The electron transfer catalysis by flavonoids

Flavonoids readily participate in biological oxidation-reduction processes and thus, are effective catalysts of electron transfer reactions. This implies firstly that their physiological standard potentials are located near that of important biochemical oxidation/reduction couples and secondly, that their activation energies for the uptake or donation of electrons are low. Since flavonoids are inactivated by oxidation, they much more easily lose than gain an electron. In this connection, it is

The flavonoids as enzyme inhibitors

Numerous enzymes, some of which were mentioned in Section 11, are inhibited by flavonoids. They include hydrolases, oxidoreductases, DNA synthetases, RNA polymerases, phosphatases, protein phosphokinases, oxygenase, and amino acid oxidases. This list is probably not complete since frequently new reports appear on additional examples of enzyme inhibitions by these substances. In some cases, the type of inhibition is competitive, but more often it is allosteric. Examples of allosteric activation

The hormone action of flavonoids

Flavonoids can act as hormones in both plants and animals Sonnenbichler et al., 1980, Sonnenbichler & Pohl, 1980, Baker, 1998, Baker et al., 1998. The roles of flavonoids as plant hormones already have been discussed (see Section 6). The discovery that flavonoids also have hormonal effects in animal systems was a surprise (Mitcher et al., 1982). The origin was the observation that sheep that had eaten fermented clover became sexually aroused. An analysis showed that the active substance was

The mutagenic potential of flavonoids

Many organic substances, regardless of whether they are natural products or prepared synthetically, are capable of inducing mutation in the Ames test Ames et al., 1975, MacGregor & Jurd, 1978, MacGregor, 1979, MacGregor, 1986a, MacGregor, 1986b, Brown et al., 1977, Brown, 1980, Bjeldanes & Chang, 1977, Hatcher & Bryan, 1985, Ellinger et al., 1984, Bartholomew & Ryan, 1980, which indicates that they are potentially mutagenic in humans. Since the experimental conditions of this test are far

The influence of the flavonoids on the sensory system

The human sensory system continuously registers and reports the state of the internal and the external environment. Examples are the fragrance of flowers, the taste of a spiced meal, the aroma of freshly brewed coffee, and the bouquet of a wine. All of these sensations, which each in its own way improves the quality of life, are, to a considerable extent, liberated by flavonoids that have been entrained with water vapours and other volatile substances. In other words, not only the colors from

Complexes of flavonoids with heavy metal ions

Heavy metal ions are avid ligand binders Asen et al., 1977, Hiermann & Kartnig, 1978, Middleton & Drzewiecki, 1982, Schwartz et al., 1982, Schwartz & Middleton, 1984, Miura et al., 1994. This ability is also evident in many biological systems. Examples are hemoproteins, cobalamine (i.e., vitamin B12), and numerous metalloenzymes (Parellada et al., 1998). Among the heavy metal atoms that are essential to biochemical systems are Fe2+, Cu2+, Zn2+, Co+1, Mn2+, and Ni2+. However, other heavy metal

Medical, technical, gastronomic, and other applications of flavonoids

The use of bee products, such as honey, propolis (kit wax), wax, gelé royal, and pollen, in the treatment of human diseases is very old. It is probably almost as old as humanity itself, i.e., about two million years (Eversted et al., 1997). All of these bee products contain appreciable concentrations of flavonoids, especially propolis, which is a rich source of flavonoids. Honey was probably the first of the bee product that was eaten because its taste is sweet and its high glucose

Interaction of flavonoids with other drugs

Drug interactions create increasing problems to the design and control of modern medical treatments, as new insights into pathogenesis lead to the introduction of ever more complex drugs. Thus, the mutual interaction between two drugs or between a drug and a food component, e.g., alcohol, can drastically displace the therapeutic window of one or both of the drugs and, thus, render them useless or dangerous. Although the flavonoids are considered as nontoxic components of common foods, they can

Prospects of further applications of flavonoids

The use of flavonoids for the prevention and cure of diseases is already widespread. The conscious use of these substances is more common in the developing and in the emerging countries than in the industrialised part of the world. In the latter, the demands by the medical authorities on the proven efficiency and safety of new candidate drugs, for which authorisation is applied, are high and rigid. Hardly anybody opposes such strict rules, but the consequence is that only very few flavonoids

Acknowledgements

Thanks are due to Mrs. R. Thun for her assistance with the experimental work and to Miss S. Schiemenz for her help with the manuscript, as well as with the extensive literature search.

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