Winter 2000 Issue — Use of Bioflavonoids as Dietry Supplements

Lutz Thomas, Herwig Buchholz, Nicole Spikers and Najib Sehat

Merck KGaA, Darmstadt, Germany

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Introduction

Modern lifestyle, environmental challenges and the exploding health insurance costs drives the dietary supplement industry. The changes within the medical community, away from corrective treatment towards preventive means, and the patients demands for a choice of treatment propel the dynamics of the market. The aging baby-boomers can typically be described by their interest in physical exercise, growing health awareness and by an understanding of the health impacts of a wholesome diet. Food additives and the regular use of dietary supplements are, therefore, logical consequences and contribute to the booming growth of the respective food industry segments. In the United States one out of three households used more than seven dietary supplements in the first half of lgg7. A very similar trend has started in Europe and the health food market in Japan is almost legendary. Among the use categories that are targeted, mood shifts, absentmindedness, cardiovascular health, immune stimulation, and energy boosts are important. Nowadays, the interest in cell protection against free radicals and thus the use of natural antioxidants and radical scavengers grows tremendously. Within this group bioflavonoids, from various plant sources, take a role of growing importance. Hundreds of flavonoids and their physiological properties are described in the scientific literature. Those rather simple chemical structures are ubiquitous in the plant kingdom and are thus ingested via the food supply.

Most of the free radicals are unstable and, as a result, extremely reactive compounds. Radicals are created by environmental factors such as high energy ultraviolet rays or hazardous pollutants as well as normal metabolic processes. Once these reactants interact with cell constituents (DNA, proteins, lipids etc.), they are able to convert e.g. polyunsaturated fatty acids into free radical species. Free radicals are generated due to the break up of the double-bonds in the respective fatty acids. By the mechanism of a chain-reaction radicals from polyunsaturated fatty acids generate a dramatically growing number of radicals. Since polyunsaturated fatty acids are omnipresent in every cell of the body and specifically in the cell membranes this process, called lipid peroxidation, can affect all tissues and organs. The consequences of the various types of radical reactions, especially with oxygen superoxides and singlet oxygen, were shown to have high impacts on the body's function. This is well documented and ranges from accelerating aging to nearly all non-contagious diseases. Today's role of flavonoids in nutrition has been established with our understanding of the necessity to prevent oxidative stress and cellular damage. Flavonoids have the ability to interact with free radicals, convert them to less reactive species and thus reduce the harmful consequences of oxidative stress and radical exposure. The efficacy of fat soluble flavonoids as antioxidants and radical scavengers is in part due to the presence of multiple hydroxyl groups and the conjugated structure of the system. The combination of the phenolic systems in the flavonoids allows efficient reactions with radicals, yielding harmless oxidized flavonoid species and thus protection of the essential cell components.

The bioflavonoids rutin and quercetin have a long history of safe use in the dietary supplement and medical field. Other bioflavonoids such as isoquercetin and luteolin are on the brink of introduction into the various markets.

Scheme 1 The Bioflavonoids Rutin, Isoquercetin and Quercetin

Rutin is a flavonol glycoside comprised of the flavonol backbone and the glycon rutinose, see scheme 1. It is widely spread in the plant kingdom and is found in high concentrations in fruit and vegetables, such as oranges, apples and tomatoes. Other plant sources utilized for the industrial extraction of rutin are Sophora and Dimorphandra, which grow e.g. in China and Brazil. Rutin is a yellowish, microcrystalline powder, which is completely tasteless and thus suitable for use as dietary supplement. Numerous formulations, e.g. with vitamins, are available in the market. Rutin is used systemically but also topically in cremes and ointments that are applied to stimulate blood circulation and reduce capillary fragility in the body extremities.

The antioxidant properties of rutin substantially exceed those of other technical antioxidants. Protection equals more than twice the antioxidative strength of Trolox, a watersoluble Vitamin E analogue, which is used in an established test to determine antioxidative potency (TEAC-test). Rutin is the basis of a whole group of bioflavonoids. By enzymatic hydrolysis, and specifically the cleavage of the glycosidic bond between the flavonol and its glycon, the bioflavonoid quercetin and the disaccharide rutinose are obtained. Rutinose can further be degraded into the monosaccharide rhamnose. Rhamnose is an interesting raw material for the flavor and fragrance industry. In addition, the cleavage between the two sugar moieties results in the natural flavonoid isoquercetin.

Quercetin has even stronger antioxidant and radical scavenging characteristics than rutin. Quercetin's antioxidant activity is almost five times that of TroloxiG. Quercetin is a superior antioxidant towards free radicals and especially reactive oxygen species. The cytoprotective properties are the main reason for quercetin's dietary use. Similar to rutin, various studies have also shown strong effects of quercetin on cardiovasculat health. Typically quercetin is formulated into dietary supplement products together with ascorbic acid. Both products' antioxidative capabilities work synergistically since quercetin also protects cellular vitamin E from oxidation and is itself regenerated by ascorbic acid.

All of the described flavonoids share the same aglycon, quercetin. In isoquercetin the 3 position is glycosidically linked to glucose in its pyranoside form. If the glucose moiety is bound in the furanoside configuration, the resulting bioflavonoid is isoquercitrine. Recent research has shown a rapid absorption of isoquercetin and quercetin-glycosides in general in the small intestine by a glucose dependant transport mechanism. Therefore isoquercetin shows an increased bloavailability and enhanced pharmacokinetics over quercetin. The blood levels of isoquercetin peakievel after a much shorter absorption time than other related bioflavonoids. As a matter of fact, the maximum levels are reached in only a few hours. The downside of the faster uptake into the plasma is the lower antioxidant capacity of isoquercetin versus quercetin. Isoquercetin has a similar antioxidant activity to rutin and only 50% of the quercetin potency. Once absorbed isoquercetin is enzymatically split into quercetin and glucose, quercetin can subsequently exhibit its full antioxidative power.

Bioflavonoids can be used as safe antioxidants to prevent damages caused by free radicals. The ubiquitous presence of bioflavonoids in the vegetable food supply should be supplement by the means of dietary supplements for protection from the inside. The combined use of a variety of bioflavonoids in nutrition and cosmetics will help to maintain health and thus to ensure a better life.

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