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dc.contributor.authorManzella, Adam
dc.date.accessioned2016-03-21T20:13:31Z
dc.date.available2016-03-21T20:13:31Z
dc.date.issued2007
dc.identifier.isbn9780549173625
dc.identifier.other304764870
dc.identifier.urihttp://hdl.handle.net/10477/42640
dc.description.abstractPolychlorinated biphenyls (PCBs) are persistent human contaminants previously used in transformer fluids, hydraulic fluids, flame-retardants and a variety of other industrial products (ATSDR 2000). Besides having the ability to bioaccumulate in the fatty tissues of humans, PCBs elicit a variety of adverse biological responses. Polybrominated diphenyl ethers (PBDEs) are a group of brominated flame-retardants that have been used as additives in a wide variety of consumer products since the 1970's. The biological responses of PBDEs are less understood, but due to their structural similarity with PCBs, the same types of responses can be predicted. PCBs and PBDEs enter the cell through diffusion but little is known about the efflux transport of these compounds. In this study, the in vitro model being used is the MCF7/MX100 cell line which specifically over expresses only breast cancer resistance protein (ABCG2). Utilization of this cell line allows one to look exclusively at the potential of PCBs and PBDEs to modulate drug efflux transporter ABCG2 transporter function. This is accomplished using a specific substrate of ABCG2, mitoxantrone and the ABCG2 inhibitor 7,8-benzoflavone. Flow cytometry is utilized to quantify the amount of mitoxantrone accumulation in the cells after treatment with various concentrations of the non-ortho substituted PCB126, di -ortho substituted PCB153, PCB47, PBDE153, PBDE47 and mono-ortho substituted PCB28, PCB74 and PCB118. Various PCBs and PBDEs inhibited the efflux of mitoxantrone in a concentration-related manner, suggesting that they are inhibitors of the ABCG2 transporter. Treatment with 50uM 2,2 ́,4,4 ́-tetrachlorobiphenyl (PCB47), a di -ortho substituted PCB, produces a 6-fold increase in concentration of mitoxantrone in MCF7/MX100 cells, which suggests that this congener is an effective inhibitor of the ABCG2 transporter. Other di -ortho and mono -ortho substituted PCBs and PBDEs have been examined and found to be, to varying degrees, inhibitors for ABCG2. This study is the first to show that PCBs and PBDEs are inhibitors of the ABCG2 transporter. The results will not only provide further mechanistic data of potential significance regarding the disposition and excretion of PCBs and PBDEs but provide new insight on potential toxicological responses of these contaminants which may in part be related to inhibition of this important transporter.
dc.languageEnglish
dc.subjectHealth and environmental sciences
dc.titleStructure dependent characterization of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) as inhibitors of the breast cancer resistance protein (ABCG2) transporter
dc.typeDissertation/Thesis


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