Document Detail


Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain.
MedLine Citation:
PMID:  12358729     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Renal impairment is associated with CNS dysfunctions and the accumulation of uremic toxins, such as indoxyl sulfate, in blood. To evaluate the relevance of indoxyl sulfate to CNS dysfunctions, we investigated the brain-to-blood transport of indoxyl sulfate at the blood-brain barrier (BBB) using the Brain Efflux Index method. [(3)H]Indoxyl sulfate undergoes efflux transport with an efflux transport rate of 1.08 x 10(-2)/min, and the process is saturable with a Km of 298 microm. This process is inhibited by para-aminohippuric acid, probenecid, benzylpenicillin, cimetidine and uremic toxinins, such as hippuric acid and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. RT-PCR revealed that an OAT3 mRNA is expressed in conditionally immortalized rat brain capillary endothelial cell lines and rat brain capillary fraction. Xenopus oocytes expressing OAT3 were found to exhibit [(3)H]indoxyl sulfate uptake, which was significantly inhibited by neurotransmitter metabolites, such as homovanillic acid and 3-methoxy-4-hydroxymandelic acid, and by acyclovir, cefazolin, baclofen, 6-mercaptopurine, benzoic acid, and ketoprofen. These results suggest that OAT3 mediates the brain-to-blood transport of indoxyl sulfate, and is also involved in the efflux transport of neurotransmitter metabolites and drugs. Therefore, inhibition of the brain-to-blood transport involving OAT3 would occur in uremia and lead to the accumulation of neurotransmitter metabolites and drugs in the brain.
Authors:
Sumio Ohtsuki; Hiroshi Asaba; Hitomi Takanaga; Tsuneo Deguchi; Ken-ichi Hosoya; Masaki Otagiri; Tetsuya Terasaki
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  83     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2002 Oct 
Date Detail:
Created Date:  2002-10-02     Completed Date:  2002-10-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  57-66     Citation Subset:  IM    
Affiliation:
Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antimetabolites / pharmacology
Biological Transport / drug effects,  physiology
Blood-Brain Barrier / drug effects,  physiology*
Brain / blood supply,  metabolism*
Capillaries / cytology,  metabolism
Cells, Cultured
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Endothelium, Vascular / cytology,  metabolism
GABA Agonists / pharmacology
Homovanillic Acid / pharmacology
Indican / metabolism*,  pharmacokinetics
Male
Microinjections
Neurotransmitter Agents / metabolism*
Oocytes / metabolism
Organic Anion Transporters, Sodium-Independent / genetics,  metabolism*
RNA, Messenger / biosynthesis
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Uremia / metabolism
Xenopus laevis
p-Aminohippuric Acid / pharmacology
Chemical
Reg. No./Substance:
0/Antimetabolites; 0/GABA Agonists; 0/Neurotransmitter Agents; 0/Organic Anion Transporters, Sodium-Independent; 0/RNA, Messenger; 0/organic anion transport protein 3; 306-08-1/Homovanillic Acid; 487-94-5/Indican; 61-78-9/p-Aminohippuric Acid

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