Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Incidences of breast, colorectal and prostate cancer are high in the Western world compared to countries in Asia. We have postulated that the Western diet compared to the semivegetarian diet in some Asian countries may alter hormone production, metabolism or action at the cellular level by some biochemical mechanisms. Our interest has been focused on two groups of hormone-like diphenolic phyto-oestrogens of dietary origin, the lignans and isoflavonoids abundant in plasma of subjects living in areas with low cancer incidence. The precursors of the biologically active compounds detected in man are found in soybean products, whole-grain cereal food, seeds, and berries. The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormone-like compounds. The weakly oestrogenic diphenols formed influence sex-hormone production, metabolism and biological activity, intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, cell adhesion and angiogenesis in such a way as to make them strong candidates for a role as natural cancer-protective compounds. Their effect on some of the most important steroid biosynthetic enzymes may result in beneficial modulation of hormone concentrations and action in the cells preventing development of cancer. Owing to their oestrogenic activity they reduce hot flushes and vaginal dryness in postmenopausal women and may to some degree inhibit osteoporosis, but alone they may be insufficient for complete protection. Soy intake prevents oxidation of the low-density lipoproteins in vitro when isolated from soy-treated individuals and affect favourably plasma lipid concentrations. Animal experiments provide evidence suggesting that both lignans and isoflavonoids may prevent the development of cancer as well as atherosclerosis. However, in some of these experiments it has not been possible to separate the phyto-oestrogen effect from the effect of other components in the food. The isoflavonoids and lignans may play a significant inhibitory role in cancer development particularly in the promotional phase of the disease, but recent evidence points also to a role in the initiation stage of carcinogenesis. At present, however, no definite recommendations can be made as to the dietary amounts needed for prevention of disease. This review deals with all the above-mentioned aspects of phyto-oestrogens.

Phyto-oestrogens and Western Diseases

Phenolics in Food and Nutraceuticals is the first single-source compendium of essential information concerning food phenolics. This unique book reports the classification and nomenclature of phenolics, their occurrence in food and nutraceuticals, chemistry and applications, and nutritional and health effects. In addition, it describes antioxidant activity of phenolics in food and nutraceuticals as well as methods for analysis and quantification. Each chapter concludes with an extensive bibliography for further reading. Food scientists, nutritionists, chemists, biochemists, and health professionals will find this book valuable.

Phenolics in food and nutraceuticals

Equol [7-hydroxy-3-(4'-hydroxyphenyl)-chroman] is a nonsteroidal estrogen of the isoflavone class. It is exclusively a product of intestinal bacterial metabolism of dietary isoflavones and it possesses estrogenic activity, having affinity for both estrogen receptors, ERalpha and ERbeta. Equol is superior to all other isoflavones in its antioxidant activity. It is the end product of the biotransformation of the phytoestrogen daidzein, one of the two main isoflavones found in abundance in soybeans and most soy foods. Once formed, it is relatively stable; however, equol is not produced in all healthy adults in response to dietary challenge with soy or daidzein. Several recent dietary intervention studies examining the health effects of soy isoflavones allude to the potential importance of equol by establishing that maximal clinical responses to soy protein diets are observed in people who are good "equol-producers." It is now apparent that there are two distinct subpopulations of people and that "bacterio-typing" individuals for their ability to make equol may hold the clue to the effectiveness of soy protein diets in the treatment or prevention of hormone-dependent conditions. In reviewing the history of equol, its biological properties, factors influencing its formation and clinical data, we propose a new paradigm. The clinical effectiveness of soy protein in cardiovascular, bone and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol. The failure to distinguish those subjects who are "equol-producers" from "nonequol producers" in previous clinical studies could plausibly explain the variance in reported data on the health benefits of soy.

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The Clinical Importance of the Metabolite Equol—A Clue to the Effectiveness of Soy and Its Isoflavones

Phytoestrogens: the biochemistry, physiology, and implications for human health of soy isoflavones.

Lignans have, until recently, been found only in plants. Enterolactone and enterodiol are the major lignans present in the urine of humans and have a potential physiological protective role against cancer. It has been shown that these compounds can be formed in vitro by human faecal flora and that enterodiol is oxidized to enterolactone by bacteria that are present in stools at a concentration of up to 103/g. It was also possible to produce both of these lignans in vitro from linseeds and from secoisolariciresinol, a precursor present in linseed, by bacteria present in stools, at a concentration of between 103 and 104/g. Enterolactone was produced from matairesinol, a more abundant plant lignan than secoisolariciresinol, after incubation with a mixed faecal flora under both aerobic and anaerobic conditions. In each case conversion was dependent on the presence of viable bacteria. These findings indicate that a number of different pathways operate to produce enterolactone and enterodiol depending on the ingested dietary precursor.

Production and metabolism of lignans by the human faecal flora.

The identification (by gas chromatography–mass spectrometry and n.m.r.) for the first time of the weak oestrogen equol [7-hydroxy-3-(4′-hydroxyphenyl)chroman] in human urine is described. Preliminary results of its quantitative excretion in urine are reported and the potential significance of the occurrence of this compound is discussed.

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The identification of the weak oestrogen equol [7-hydroxy-3-(4′-hydroxyphenyl)chroman] in human urine

The definitive identification of the first lignans to be found in humans and animals is described. Gas chromatography--mass spectrometry, n.m.r. spectroscopy, i.r. spectroscopy and chemical techniques were employed to establish the structures of two lignans as trans-2,3-bis(3-hydroxybenzyl)-gamma-butyrolactone and 2,3-bis(3-hydroxybenzyl)butane-1,4-diol. Both compounds are essetially racemic. Evidence was also found for several methoxy analogues of these lignans in the vervet monkey.

The definitive identification of the lignans trans-2,3-bis(3-hydroxybenzyl)-gamma-butyrolactone and 2,3-bis(3-hydroxybenzyl)butane-1,4-diol in human and animal urine.

K. D. R. Setchell

Papers

Production and metabolism of lignans by the human faecal flora.

The identification of the weak oestrogen equol [7-hydroxy-3-(4′-hydroxyphenyl)chroman] in human urine

The definitive identification of the lignans trans-2,3-bis(3-hydroxybenzyl)-gamma-butyrolactone and 2,3-bis(3-hydroxybenzyl)butane-1,4-diol in human and animal urine.

Synthesis of the deuterium-labeled urinary lignans enterolactone and enterodiol