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Coordinate Regulation of Uptake and Efflux Transporters
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abstract
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Elucidating the mechanisms by which chemicals and drugs are taken up into and eliminated from cells can enhance the understanding of drug bioavailability and can aid in prediction of tissue-specific distribution and toxicity of drugs. Organic anion transporting polypeptide (Oatp) and multidrug resistance-associated protein (Mrp) transporters mediate uptake and efflux, respectively, of a wide variety of substrates in liver. Coordinate regulation of uptake and efflux transporters may be a mechanism by which cells protect themselves from chemicals, for example, by simultaneously decreasing entrance and enhancing elimination of chemicals. Perflourodecanoic acid (PFDA) is a ten-carbon fluorinated fatty acid and a component of numerous commercial products. PFDA is a peroxisome proliferator that also produces a broad spectrum of toxicity in rodents. Our own experiments have demonstrated that PFDA causes unique and dramatic changes in hepatic expression of Oatp and Mrp transporters. These PFDA-mediated changes in transporter expression are likely to have physiological implications by affecting hepatic uptake and elimination of both endogenous and xenobiotic substrates. These novel effects of PFDA on transporter gene expression thus merit further investigation. Therefore, PFDA can be used as a powerful tool to elucidate mechanisms of transporter regulation. To further our knowledge of transporter regulation by PFDA, we propose the following studies: 1) examine alterations in transporter gene expression as a function of both dose and time, 2) determine the effects of these changes in gene expression on xenobiotic distribution, and 3) examine the contribution of several key transcription factors in the regulation of transporters by PFDA. The studies proposed will increase our understanding of the unique and dramatic effects of PFDA on transporter genes and on the consequences of altering transporter gene expression. More generally, these investigations will elucidate mechanisms of transporter gene regulation, information that is important in predicting possible therapeutic benefits of transporter modulation, as well as possible drug-drug interactions in humans.
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