| Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PDBEs) are structurally similar persistent organic pollutants (POPs) that elicit a variety of biological and toxicological responses. The Breast Cancer Resistance Protein (ABCG2) is a novel 72 kDa protein, which is expressed largely in the organs responsible for absorption and elimination of xenobiotics, and plays an important role in drug disposition and is known to be a major factor of drug resistance (Koshiba 2008). In this study, the in vitro model being used is the MCF7/MX100 cell line, which specifically over expresses only ABCG2 which allows one to look exclusively at the impact that exposure to PCBs and PBDEs will have, upon the transporters ability to efflux a specific substrate of ABCG2, mitoxantrone. Flow cytometry, was used to quantify the relative accumulation of mitoxantrone within the cells after exposure to a given PCB or PBDE, and compared that to the mitoxantrone level in control cells and cells exposed to 7, 8-benzoflavone, a specific inhibitor of ABCG2. Exposure to PCB 47 (2, 2', 4, 4') at concentrations of, 0.1, 1.0, 5.0, 10, 25 and 50 muM produced a 1.4, 1.9, 4.1, 5.4, 5.5 and 6.8 fold increase, respectively. Similarly, exposure to PBDE 47 (2, 2', 4, 4') at concentrations of, 0.1, 1.0, 5.0, 10 and 25 muM produced a 1.2, 1.9, 2.8, 3.3, and 3.8 fold increase, respectively. PCB 47 and PBDE 47 have IC50 values of 4.18 muM and 8.7 muM, respectively, suggesting that PCB 47 is a more potent and active inhibitor of ABCG2. In vitro exposure to other PCBs and PBDEs, inhibit to a variable extent the efflux transport of mitoxantrone and suggests that these compounds exhibit congener-specificity as inhibitors of ABCG2. Preliminary studies using GC/ECD were performed to determine if the most potent and efficacious inhibitor identified by this research, PCB 47, is actually a substrate for ABCG2. These studies showed no significant difference in the intracellular percentage of PCB 47 in MCF7/MX100 cells with or without the presence of the inhibitor 7,8-benzoflavone. However, more studies are needed to assess whether these compounds are also substrates for the ABCG2 transporter. The results of this study provide new insights into the effect that these compounds play on the inhibition of the ABCG2 drug transporter, which may in turn alter the disposition and excretion of xenobiotics. |
