Potential health impacts of excessive flavonoid intake

Abstract

Plant flavonoids are common dietary components that have many potent biological properties. Early studies of these compounds investigated their mutagenic and genotoxic activity in a number of in vitro assays. Recently, a renewed interest in flavonoids has been fueled by the antioxidant and estrogenic effects ascribed to them. This has led to their proposed use as anticarcinogens and cardioprotective agents, prompting a dramatic increase in their consumption as dietary supplements. Unfortunately, the potentially toxic effects of excessive flavonoid intake are largely ignored. At higher doses, flavonoids may act as mutagens, pro-oxidants that generate free radicals, and as inhibitors of key enzymes involved in hormone metabolism. Thus, in high doses, the adverse effects of flavonoids may outweigh their beneficial ones, and caution should be exercised in ingesting them at levels above that which would be obtained from a typical vegetarian diet. The unborn fetus may be especially at risk, since flavonoids readily cross the placenta. More research on the toxicological properties of flavonoids is warranted given their increasing levels of consumption.

Introduction

Plant flavonoids are diphenylpropane derivatives that exert a wide range of biochemical and pharmacological effects. Their antioxidant properties [1], [2], cytostatic effects in tumorigenesis [3], and ability to inhibit a broad spectrum of enzymes, such as protein kinase C [4], tyrosine protein kinase [5], and topoisomerase II [6], [7], have led researchers to regard these compounds as potential anticarcinogens and cardioprotective agents. These findings have contributed to the dramatic increase in the consumption and use of dietary supplements containing high concentrations of plant flavonoids by some health-conscious individuals. Marketing strategies by manufacturers of flavonoid concentrates and herbal remedies advertise and often exaggerate their nontoxic therapeutic effects, most of which are not substantiated by regulated clinical trials. Furthermore, manufacturers’ recommended doses of these products might far exceed the flavonoid dose one could attain from a typical vegetarian diet. This, coupled with the common misconception that if a little of something is good then more is better, may result in individuals ingesting extremely high levels of these compounds.

Despite the apparently beneficial health effects of flavonoids, several studies indicate their mutagenicity and genotoxicity in both bacterial and mammalian experimental systems [8], [9], [10] (Table 1). This may be due to their activity as pro-oxidants [11], [12] in generating free radicals that damage DNA or their inhibition of DNA-associated enzymes such as topoisomerase. Unrepaired or misrepaired oxidative DNA damage can result in DNA strand breaks and mutations [13], [14] that may lead to irreversible preneoplastic lesions. Furthermore, high intakes of these compounds may potentiate other deleterious effects due to their diverse pharmacological properties, which may alter drug and amino acid metabolism, modulate the activity of environmental genotoxicants, and alter the activity of other key metabolizing enzymes. While there is ample evidence that a flavonoid-rich diet may promote good health and provide protection from age-related diseases, there remains uncertainty regarding the conditions and the levels of flavonoid intake necessary to pose a potential health hazard. Therefore, this review will seek to evaluate the potential toxicity of some of these compounds, particularly at levels higher than those generally found in a normal diet, but which may be attained through supplementation of plant extracts.