Gender-Dependent Metabolism of Flavonoids as a Possible Determinant of Cancer Risk

To date, more than 6000 structurally different flavonoids have been described in nature being widely distributed in plant origin foods and possessing a vast potential for mammalian defense against different chronic diseases, such as malignancies. However, application of anticancer properties of flavonoids in pharmaceutical field and clinical settings is still hindered by their poor bioavailability that is defined as the fraction of administered bioactive compound entering the systemic circulation in unchanged form, i.e. without structural modifications [10]. Indeed, the plasma concentrations of parent flavonoids in humans are very low and significantly below the doses needful for therapeutic effects; or in other words, pharmacologically effective concentrations of these phytopigments are mostly not achievable through the dietary consumption [6,8,11-13]. For instance, the baseline plasma concentrations of flavonol quercetin from dietary sources are about 50-80 nM remaining considerably lower than the cytotoxically active doses [14-16]. Similarly, the peak plasma concentration of green tea flavanol epigallocatechin gallate (EGCG) is only about 150 nM after drinking two cups of green tea being certainly not sufficient for exerting anticancer activities [14,17]. The major drawbacks for such a low oral bioavailability of flavonoids include limited water solubility and stability, poor absorption across gastrointestinal epithelial cells, and extensive and rapid metabolic bioconversion of these plant-derived edible agents in the small intestine and liver, mainly via glucuronidation and/or sulfation conjugations [9]. Moreover, there are several evidences demonstrating that bioavailability of flavonoids depends also on the host related factors, including gender and age/maturity of the individual subjects [12]. In this way, the capacity of liver metabolism of flavonoids has been reported to be determined by the gender of rats [9]. Indeed, studies on the metabolism of flavone apigenin in Wistar rats revealed clear differences between male and female animals with regard to the proportion of glucuronidated and sulfated derivatives eliminated via urinary route, probably explained by the genderspecific regulation of certain phase I and II metabolic enzymes [18]. Similarly, gender was shown to significantly affect also the sulfation of monohydroxyflavones in rat and mouse liver S9 fractions [19]. However, gender differences in bioconversion of flavonoids have still drawn only little attention so far and certainly need further investigation and experimental evidences both relating to the nature and anticancer properties of circulating metabolites. It is evident that actual physiological responses are mediated by the enzymatic products reaching to bloodstream rather than the respective parent flavonoids. At that, it is also important to bear in mind that results obtained with animals (rodents) may not be directly extrapolated to humans [19,20]. Therefore, much work is needed to be accomplished in the issue of gender-dependent metabolism of flavonoids in humans as well as the changes in anticancer efficacy of metabolites formed during such bioconversion. Also, the gender-specific genetic Editorial