Associate editor: S.T. Mayne
Dietary agents in cancer prevention: flavonoids and isoflavonoids

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Abstract

Flavones and isoflavones may play a prominent role in cancer prevention since these compounds are found in numerous plants that are associated with reduced cancer rates. This article reviews recent epidemiological and animal data on isoflavones and flavones and their role in cancer prevention. It covers aspects of the bioavailability of these dietary constituents and explores their mechanism of action. Human epidemiology data comes primarily from studies in which foods rich in isoflavones or flavones are associated with cancer rates. This approach has been particularly useful with isoflavones because of their abundance in specific foods, including soy foods. The bioavailability of flavones and isoflavones has been shown to be influenced by their chemical form in foods (generally glycoside conjugates), their hydrophobicity, susceptibility to degradation, the microbial flora of the consumer, and the food matrix. Some information is available on how these factors influence isoflavone bioavailability, but the information on flavones is more limited. Many mechanisms of action have been identified for isoflavone/flavone prevention of cancer, including estrogenic/antiestrogenic activity, antiproliferation, induction of cell-cycle arrest and apoptosis, prevention of oxidation, induction of detoxification enzymes, regulation of the host immune system, and changes in cellular signaling. It is expected that some combination of these mechanisms will be found to be responsible for cancer prevention by these compounds. Compelling data suggest that flavones and isoflavones contribute to cancer prevention; however, further investigations will be required to clarify the nature of the impact and interactions between these bioactive constituents and other dietary components.

Introduction

Epidemiological studies have consistently shown an inverse association between consumption of vegetables and fruits and the risk of human cancers at many sites Block et al., 1992, Messina et al., 1998, Steinmetz & Potter, 1991a. There are many plausible mechanisms by which intake of vegetables and fruits may prevent carcinogenesis. Plant foods contain a wide variety of anticancer phytochemicals with many potential bioactivities that may reduce cancer susceptibility Waladkhani & Clemens, 1998, Wattenberg, 1992a, Wattenberg, 1992b, Steinmetz & Potter, 1991b, Adlercreutz, 1990. Flavonoids and isoflavonoids are especially promising candidates for cancer prevention Bravo, 1998, Kuo, 1997, Potter & Steinmetz, 1996, Knight & Eden, 1996, Hollman et al., 1997, Knekt et al., 1997, Adlercreutz, 1995.

Flavonoids are plant secondary metabolites, present in all terrestrial vascular plants. Flavonoids are defined chemically as substances composed of a common phenylchromanone structure (C6C3C6), with one or more hydroxyl substituents, including derivatives (Table 1). In marked contrast to flavonoids, isoflavonoids possess a 3-phenylchroman skeleton that is biogenetically derived from the 2-phenylchroman skeleton of the flavonoids. Isoflavonoids are found in plants of the subfamily Papilionoideae of the Leguminosae, which includes soybeans (Harborne, 1989). Flavonoids and isoflavonoids occur commonly as ester, ether, or glycoside derivatives or mixtures thereof, and embrace over 4000 compounds (Harborne, 1989). In mammals, flavonoids and isoflavonoids occur only through dietary intake. The average daily human intake of flavonoids in the United Kingdom and the United States has been estimated to be 20 mg to 1 g. These compounds are present in fruits, vegetables, grains, nuts, tea, and wine (Pierpoint, 1986).

Flavonoids and isoflavonoids have shown many biological properties that may account for cancer chemoprevention Bravo, 1998, Kuo, 1996, Birt et al., 1999, Messina et al., 1998, Adlercreutz, 1995. In recent years, considerable attention has been paid to their abilities to inhibit the cell cycle, cell proliferation, and oxidative stress, and to induce detoxification enzymes, apoptosis, and the immune system. In view of heightened interest in the biological effects of flavonoids and isoflavonoids, the time was appropriate to review the current knowledge of the epidemiology, anticarcinogenic activity, bioavailability, and potential mechanisms of action of flavonoids and isoflavonoids. Building upon this foundation will facilitate development of new strategies and approaches for cancer control.

Section snippets

Epidemiology

Studies relating flavonoid and isoflavonoid intake to cancer rates have assessed the relationship of food groups rich in these compounds to cancer risk. Currently, no intervention trials have been conducted. A large body of data has demonstrated the importance of plant intake in reducing cancer risk (Steinmetz et al., 1994). Because flavonoids and isoflavonoids are found in particular foods, studies relating specific foods to cancer have been used to develop hypotheses on the importance of

Anticarcinogenesis

Studies of cancer prevention in experimental animals have assessed the impact of a wide variety of flavonoids and a select few isoflavones for their efficacy in inhibiting cancer in a number of animal models.

As in other studies of dietary prevention of cancer, models of breast and colon cancers have been prominent in assessing cancer prevention by flavonoids and isoflavonoids. Citrus flavonoids were the focus of studies by So et al. (1996). They determined the impact of hesperetin and

Application of general principles of bioavailability to flavonoids and isoflavonoids

Bioavailability is defined operationally and pharmacologically as the proportion of the compound administered intravenously that appears in plasma over time (measured as area under the curve) when the compound is administered orally. This represents the proportion of the compound that is absorbed from the gastrointestinal (GI) tract. Bioavailability from a nutritionist's viewpoint is often expressed as the proportion of an ingested dose that is excreted in urine compared with the proportion

Estrogenic and antiestrogenic activity

The estrogenic activity of isoflavonoids was first noted in the 1940s when clover pastures rich in isoflavones were proposed to be responsible for infertility of sheep in Western Australia (Bennets et al., 1946). Since then, a list of isoflavonoids, including genistein, daidzein, and formononetin, have been shown to be estrogenic agonists in various animal models Moule et al., 1963, Farnsworth et al., 1975. By using an estrogen receptor-dependent transcriptional response assay, Miksicek (1993)

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