Associate editor: S.T. MayneDietary agents in cancer prevention: flavonoids and isoflavonoids
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 (C6C3C6), 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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