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THE ROLE OF FLAVONOIDS IN MODULATION OF THE METABOLISM OF ARSENIC
Citation:
DROBNA, Z., A. H. ZAVALA, F. WALTON, D. J. THOMAS, AND M. STYBLO. THE ROLE OF FLAVONOIDS IN MODULATION OF THE METABOLISM OF ARSENIC. Presented at Society of Toxicology Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
To examine effects of sub-toxic concentrations of two isoflavone compounds, genistein (MRPs and P-gp inhibitor) and phloretin (AQP9 and GLUT inhibitor), on the transport and metabolism of arsenite [iAs(III)] and methylarsonous acid [MAs(III)] in human hepatocellular carcinoma (HepG2) cells.
Description:
The biotransformation of inorganic arsenic (iAs) in humans produces trivalent and pentavalent methylated species. The pattern and extent of iAs conversion is critical for the overall toxicity and adverse health effects associated with arsenic exposure. Our previous work showed a strong correlation between the rate of iAs methylation by primary human hepatocytes and the amount of arsenic retained in cells, suggesting that membrane transporters that regulate the uptake of iAs and/or efflux of its metabolites play a key role in determining the capacity of human liver, to methylate iAs. Aquaglyceroporin 9 (AQP9) and the glucose transporter GLUT1 have been identified as the membrane transporters that are responsible for the uptake of iAs by mammalian cells. The multidrug resistance-associated proteins (MRPs) and P-glycoprotein (P-gp) have been shown to mediate the efflux of iAs metabolites. Several reports have shown that the expression and activity of all the above transporters can be modulated by a variety of nutrients. We have examined effects of sub-toxic concentrations of two isoflavone compounds, genistein (MRPs and P-gp inhibitor) and phloretin (AQP9 and GLUT inhibitor), on the transport and metabolism of arsenite [iAs(III)] and methylarsonous acid [MAs(III)] in human hepatocellular carcinoma (HepG2) cells. Our data show that GLUT1, MRP2 and P-gp are highly expressed in HepG2 cells. Exposure of HepG2 cells to genistein decreased the accumulation of iAs(III) but increased the accumulation of MAs(III). Phloretin was responsible for an increased accumulation of both iAs(III) and MAs(III). Efflux of iAs and MAs from HepG2 cells was inhibited by both genistein and phloretin, but phloretin was a more potent inhibitor than genistein. In addition, phloretin inhibited the methylation of iAs(III) and MAs(III) by HepG2 cells. These results suggest that flavonoids could play a significant role in modulation of arsenic metabolism and toxicity in human cells. (This abstract does not reflect EPA policy.)