Coordinate Regulation of Uptake and Efflux Transporters

描述（由申请人提供）：阐明化学品和药物被吸收进入细胞和从细胞中消除的机制可以增强对药物生物利用度的理解，并有助于预测药物的组织特异性分布和毒性。有机阴离子转运多肽（Oatp）和多药耐药相关蛋白（Mrp）转运蛋白分别介导肝脏中多种底物的摄取和外排。摄取和外排转运蛋白的协调调节可能是细胞保护自身免受化学品影响的机制，例如，通过同时减少化学品的进入和增强化学品的消除。全氟癸酸（PFDA）是一种十碳氟化脂肪酸，是许多商业产品的组分。PFDA是一种过氧化物酶体增殖剂，在啮齿动物中也产生广谱毒性。我们自己的实验已经证明，PFDA引起Oatp和Mrp转运蛋白的肝脏表达的独特和显着的变化。这些PFDA介导的转运蛋白表达变化可能通过影响内源性和外源性底物的肝脏摄取和消除而具有生理意义。因此，PFDA对转运蛋白基因表达的这些新作用值得进一步研究。因此，PFDA可以作为一个强有力的工具来阐明转运调控机制。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）检查转运蛋白基因表达随剂量和时间的变化，2）确定这些基因表达变化对外源性生物质分布的影响，3）检查几个关键转录因子在PFDA调控转运蛋白中的作用。提出的研究将增加我们对PFDA对转运蛋白基因的独特和显著影响以及改变转运蛋白基因表达的后果的理解。更一般地说，这些研究将阐明转运蛋白基因调控的机制，在预测转运蛋白调节可能的治疗益处以及人类可能的药物相互作用方面具有重要意义的信息。

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.