Document Detail


Physiological and molecular characterization of aristolochic acid transport by the kidney.
MedLine Citation:
PMID:  21546538     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Consumption of herbal medicines derived from Aristolochia plants is associated with a progressive tubulointerstitial disease known as aristolochic acid (AA) nephropathy. The nephrotoxin produced naturally by these plants is AA-I, a nitrophenanthrene carboxylic acid that selectively targets the proximal tubule. This nephron segment is prone to toxic injury because of 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 (mOat1, mOat2, and mOat3) as capable of mediating transport of AA-I. Kinetic analyses showed that all three transporters have an affinity for AA-I in the submicromolar range and thus are likely to operate at toxicologically relevant concentrations in vivo. Structure-activity relationships revealed that the carboxyl group is critical for high-affinity interaction of AA-I with mOat1, mOat2, and mOat3, whereas the nitro group is required only by mOat1. Furthermore, the 8-methoxy group, although 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 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 may be involved in the site-selective toxicity and renal elimination of this nephrotoxin.
Authors:
Kathleen G Dickman; Douglas H Sweet; Radha Bonala; Tapan Ray; Amy Wu
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-05
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  338     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-19     Completed Date:  2011-09-26     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  588-97     Citation Subset:  IM    
Affiliation:
Department of Pharmacological Sciences, Stony Brook University, BST-8, 152, Stony Brook, NY 11794, USA. dickman@pharm.stonybrook.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Aristolochic Acids / metabolism*,  toxicity
Biological Transport, Active / drug effects
CHO Cells
Cricetinae
Cricetulus
Kidney / drug effects,  metabolism*
Male
Mice
Mice, Inbred C3H
Organ Culture Techniques
Organic Anion Transport Protein 1 / metabolism
Organic Anion Transporters / metabolism*
Rats
Grant Support
ID/Acronym/Agency:
P01-ES004068/ES/NIEHS NIH HHS; R01 DK067216/DK/NIDDK NIH HHS; R01-DK067216/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Aristolochic Acids; 0/Organic Anion Transport Protein 1; 0/Organic Anion Transporters; 313-67-7/aristolochic acid I
Comments/Corrections

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