| Physiological and Molecular Characterization of Aristolochic Acid Transport by the Kidney. | |
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MedLine Citation:
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PMID: 21546538 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Consumption of herbal medicines derived from Aristolochia plants is associated with a progressive tubulointerstitial disease known as aristolochic acid nephropathy. The nephrotoxin produced naturally by these plants is aristolochic acid I (AA-I), a nitrophenanthrene carboxylic acid that selectively targets the proximal tubule. This nephron segment is prone to toxic injury due to its role in secretory elimination of drugs and other xenobiotics. Here we characterize the handling of AA-I by membrane transporters involved in renal organic anion transport. Uptake assays in heterologous expression systems identified murine organic anion transporters (mOats) 1, 2 and 3 as capable of mediating transport of AA-I. Kinetic analyses showed that all three transporters have an affinity for AA-I in the sub-micromolar range and thus are likely to operate at toxicologically relevant concentrations in vivo. Structure-activity relationships revealed that the carboxy group is critical for high-affinity interaction of AA-I with mOats 1, 2 and 3, whereas the nitro group is required only by mOat1. Furthermore, the 8-methoxy group, while essential for toxicity, was not requisite for transport. Mouse renal cortical slices avidly accumulated AA-I, achieving slice-to-medium concentration ratios >10. Uptake by slices was sensitive to known mOat1 and mOat3 substrates and to the organic anion transport inhibitor probenecid, which also blocked the production of DNA adducts formed with reactive intracellular metabolites of AA-I. Taken together, these findings indicate that OAT family members mediate high-affinity transport of AA-I and are likely involved in the site-selective toxicity and renal elimination of this nephrotoxin. |
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Authors:
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Kathleen G Dickman; Douglas H Sweet; Radha Bonala; Tapan Ray; Amy Wu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-5 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: - ISSN: 1521-0103 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 Stony Brook University; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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