| Glutaric aciduria type I and methylmalonic aciduria: simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. | |
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MedLine Citation:
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PMID: 20302929 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Intracerebral accumulation of neurotoxic dicarboxylic acids (DCAs) plays an important pathophysiological role in glutaric aciduria type I and methylmalonic aciduria. Therefore, we investigated the transport characteristics of accumulating DCAs - glutaric (GA), 3-hydroxyglutaric (3-OH-GA) and methylmalonic acid (MMA) - across porcine brain capillary endothelial cells (pBCEC) and human choroid plexus epithelial cells (hCPEC) representing in vitro models of the blood-brain barrier (BBB) and the choroid plexus respectively. We identified expression of organic acid transporters 1 (OAT1) and 3 (OAT3) in pBCEC on mRNA and protein level. For DCAs tested, transport from the basolateral to the apical site (i.e. efflux) was higher than influx. Efflux transport of GA, 3-OH-GA, and MMA across pBCEC was Na(+)-dependent, ATP-independent, and was inhibited by the OAT substrates para-aminohippuric acid (PAH), estrone sulfate, and taurocholate, and the OAT inhibitor probenecid. Members of the ATP-binding cassette transporter family or the organic anion transporting polypeptide family, namely MRP2, P-gp, BCRP, and OATP1B3, did not mediate transport of GA, 3-OH-GA or MMA confirming the specificity of efflux transport via OATs. In hCPEC, cellular import of GA was dependent on Na(+)-gradient, inhibited by NaCN, and unaffected by probenecid suggesting a Na(+)-dependent DCA transporter. Specific transport of GA across hCPEC, however, was not found. In conclusion, our results indicate a low but specific efflux transport for GA, 3-OH-GA, and MMA across pBCEC, an in vitro model of the BBB, via OAT1 and OAT3 but not across hCPEC, an in vitro model of the choroid plexus. |
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Authors:
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Sven W Sauer; Silvana Opp; Anne Mahringer; Marcin M Kami?ski; Christian Thiel; J?rgen G Okun; Gert Fricker; Marina A Morath; Stefan K?lker |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-17 |
Journal Detail:
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Title: Biochimica et biophysica acta Volume: 1802 ISSN: 0006-3002 ISO Abbreviation: Biochim. Biophys. Acta Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-04-26 Completed Date: 2010-06-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0217513 Medline TA: Biochim Biophys Acta Country: Netherlands |
Other Details:
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Languages: eng Pagination: 552-60 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier B.V. All rights reserved. |
Affiliation:
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Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, D-69120 Heidelberg, Germany. Sven.Sauer@med.uni-heidelberg.de |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Base Sequence Blood-Brain Barrier / physiology* Brain / metabolism* Cells, Cultured Choroid Plexus / metabolism* DNA Primers / genetics Dicarboxylic Acid Transporters / genetics, metabolism Dicarboxylic Acids / metabolism* Glutarates / urine* Glutaryl-CoA Dehydrogenase / deficiency Humans Metabolism, Inborn Errors / metabolism Methylmalonic Acid / urine* Methylmalonyl-CoA Mutase / deficiency Models, Biological Neurotoxins / metabolism RNA, Messenger / genetics, metabolism Swine |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 0/Dicarboxylic Acid Transporters; 0/Dicarboxylic Acids; 0/Glutarates; 0/Neurotoxins; 0/RNA, Messenger; 110-94-1/glutaric acid; 516-05-2/Methylmalonic Acid; EC 1.3.99.7/Glutaryl-CoA Dehydrogenase; EC 5.4.99.2/Methylmalonyl-CoA Mutase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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