MOLECULAR MECHANISMS OF DRUG/XENOBIOTIC ELIMINATION

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories, and therefore is critical for the survival of mammalian species. 5 OATs have been identified (OAT1, OAT2, OAT3, OAT4, and OAT5) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through the OAT pathway. During the previous grant period, significant progress and productivity have been achieved. We have mapped the membrane topology of OAT 1. We have identified the amino acid residues critical for OAT function. We have showed that OAT1 form homo-oligomer in kidney LLC-PK1 cells. The new findings from the previous grant period led to the establishment of a fine-tuned research plan and strategy in this competing renewal. We propose to test the central hypothesis that OATs form not only homo- but also hetero-oligomeric complexes in vivo and that transport activities of OATs are conferred by their oligomerization states. 4 Specific Aims (SAs) are outlined. In SA-1, we will determine the nature of OAT oligomerization (homo-versus hetero-oligomers). In SA-2, we will assess the importance of OAT oligomerization in maintenance of its function. In SA-3, we will dissect the molecular determinants of OAT oligomerization. In SA-4, we will compare the pharmacological and regulatory properties of OAT homo-and hetero-oligomers. Combined approaches of biochemistry, molecular biology, and biophysics will be employed for the proposed studies in tissue slices, and cultured cells. The knowledge gained from these studies will be invaluable toward the rational design of novel drugs and inhibitors to maximize therapeutic efficacy and minimize toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.