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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
Abstract
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 × 10−2/min, and the process is saturable with a Km of 298 µ m. This process is inhibited by para‐aminohippuric acid, probenecid, benzylpenicillin, cimetidine and uremic toxinins, such as hippuric acidand 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.
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Li, J. Y., Boado, R. J., & Pardridge, W. M. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200101000-00008 · Cited by 164
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Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology
VanWert, A. L., Gionfriddo, M. R., & Sweet, D. H. (2010) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.693 · Cited by 252
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Metadata
- Authors
- Ohtsuki, S., Asaba, H., Takanaga, H., Deguchi, T., Hosoya, K., Otagiri, M., & Terasaki, T.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2002-09-18
- Volume
- 83
- Issue
- 1
- Pages
- 57-66
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W1594154614
- Cited by
- 219
- References
- 1
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- closed
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- Ohtsuki, S., Asaba, H., Takanaga, H., Deguchi, T., Hosoya, K., Otagiri, M., & Terasaki, T. (2002). 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. Journal of Neurochemistry. https://doi.org/10.1046/j.1471-4159.2002.01108.x
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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