Coordinate Regulation of Uptake and Efflux Transporters

描述(申请人提供)：阐明化学品和药物被吸收和排出细胞的机制可以加强对药物生物利用度的了解，并有助于预测药物在组织中的特定分布和毒性。有机阴离子转运多肽(OATP)和多药耐药相关蛋白(MRP)转运体分别介导肝脏对多种底物的摄取和外排。对摄取和外排转运蛋白的协调调节可能是细胞保护自己免受化学物质伤害的一种机制，例如，通过同时减少进入和促进化学物质的清除。全氟十二酸(PFDA)是一种十碳氟化脂肪酸，是许多商业产品的组成成分。PFDA是一种过氧化物体增殖剂，在啮齿类动物中也会产生广泛的毒性。我们自己的实验已经证明，PFDA导致肝脏Oatp和MRP转运蛋白表达的独特和戏剧性的变化。这些PFDA介导的转运蛋白表达的变化可能通过影响肝脏对内源性和异源底物的摄取和消除而产生生理学意义。因此，PFDA对转运蛋白基因表达的这些新的影响值得进一步研究。因此，PFDA可作为阐明转运蛋白调控机制的有力工具。为了进一步了解PFDA对转运蛋白的调控，我们提出了以下研究：1)检测转运蛋白基因表达的变化作为剂量和时间的函数，2)确定这些基因表达变化对异体分布的影响，以及3)检测几个关键的转录因子在PFDA对转运蛋白的调节中的作用。建议的研究将增加我们对PFDA对转运蛋白基因的独特而戏剧性的影响以及对改变转运蛋白基因表达的后果的理解。更广泛地说，这些研究将阐明转运蛋白基因调节的机制，对于预测转运蛋白调节可能的治疗益处的重要信息，以及可能的药物-药物相互作用。

DESCRIPTION (provided by applicant): 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.