Flavonoids and gene expression in mammalian cells

Flavonoids appear to regulate the expression of many genes. As expected, when multiple flavonoids were compared in one study, structure-specificity was always observed. Unfortunately, little information is available regarding the proportion of contribution of various structural elements. Also, we have very limited information on their molecular mechanisms of action. The affinity of flavonoids for ER could explain the stimulatory effect on genes with ERE but other modes of action apparently also exist and need to be further explored. Physiological relevance is always a concern when investigating the regulation of gene expression by environmental chemicals such as flavonoids. One factor of concern is the in vivo concentration of flavonoids. Besides intestinal cells, liver cells and skin cells, other tissues obtain flavonoids through blood circulation. Thus, plasma concentrations of flavonoids are normally discussed. Steady state plasma concentrations of flavonoids are usually not much higher than 1 μM even in populations that consume large amounts of plant material. This concentration is relatively low compared to the concentrations of flavonoids that were commonly used in cell culture systems to demonstrate their effectiveness. Nevertheless, we have evidence that some flavonoids may accumulate in the cell. The effect of quercetin on metallothionein expression in Caco-2 cells persisted for at least 24 hours after its removal from the culture medium (Kuo et al., 1998). Also, long-term treatment of cultured cells with quercetin at low concentrations led to a similar effect on metallothionein expression as one high concentration treatment (Kuo et al., 2001). If intracellular accumulation of certain flavonoids is a shared characteristic for various cell types, it implies that routine ingestion of flavonoids could lead to biological effects at the concentration lower than predicted from a single treatment. Experiments to address possible cell/tissue accumulation of flavonoids are greatly needed.