Document Detail


Aristolochic acid I metabolism in the isolated perfused rat kidney.
MedLine Citation:
PMID:  22118289     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aristolochic acids are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic acid nephropathy (AAN). Aristolochic acids undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic. Previous experiments with rats showed that aristolochic acid I (AA-I), after oral administration or injection, is subjected to detoxication reactions to give aristolochic acid Ia, aristolactam Ia, aristolactam I, and their glucuronide and sulfate conjugates that can be found in urine and feces. Results obtained with whole rats do not clearly define the role of liver and kidney in such metabolic transformation. In this study, in order to determine the specific role of the kidney on the renal disposition of AA-I and to study the biotransformations suffered by AA-I in this organ, isolated kidneys of rats were perfused with AA-I. AA-I and metabolite concentrations were determined in perfusates and urine using HPLC procedures. The isolated perfused rat kidney model showed that AA-I distributes rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. It was also established that the kidney is able to metabolize AA-I into aristolochic acid Ia, aristolochic acid Ia O-sulfate, aristolactam Ia, aristolactam I, and aristolactam Ia O-glucuronide. Rapid demethylation and sulfation of AA-I in the kidney generate aristolochic acid Ia and its sulfate conjugate that are voided to the urine. Reduction reactions to give the aristolactam metabolites occur to a slower rate. Renal clearances showed that filtered AA-I is reabsorbed at the tubules, whereas the metabolites are secreted. The unconjugated metabolites produced in the renal tissues are transported to both urine and perfusate, whereas the conjugated metabolites are almost exclusively secreted to the urine.
Authors:
Horacio A Priestap; M Cecilia Torres; Robert A Rieger; Kathleen G Dickman; Tomoko Freshwater; David R Taft; Manuel A Barbieri; Charles R Iden
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2011-12-14
Journal Detail:
Title:  Chemical research in toxicology     Volume:  25     ISSN:  1520-5010     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-01-16     Completed Date:  2012-05-01     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  130-9     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Aristolochic Acids / metabolism*,  pharmacokinetics,  urine
Biotransformation
Carcinogens / metabolism*,  pharmacokinetics
Chromatography, High Pressure Liquid
Drugs, Chinese Herbal / metabolism,  pharmacokinetics
Kidney / metabolism*
Liver / metabolism
Male
Perfusion
Rats
Rats, Sprague-Dawley
Rats, Wistar
Spectrometry, Mass, Electrospray Ionization
Tandem Mass Spectrometry
Grant Support
ID/Acronym/Agency:
ES-04068/ES/NIEHS NIH HHS; P01 ES004068/ES/NIEHS NIH HHS; P01 ES004068-21/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Aristolochic Acids; 0/Carcinogens; 0/Drugs, Chinese Herbal; 313-67-7/aristolochic acid I
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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