Blood–Brain Barrier Efflux Transport of Pyrimidine Nucleosides and Nucleobases in the Rat
| Autor: | Zoran B. Redzic, Miodrag L. Rakic, Slava Malatiali, Aleksandra Isakovic, James D. Craik |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Dihydrouracil Dehydrogenase (NAD+) Pyrimidine Stereochemistry Dehydrogenase Biochemistry Nucleobase Cellular and Molecular Neuroscience chemistry.chemical_compound Dihydropyrimidine dehydrogenase Animals Tissue Distribution Rats Wistar Uracil Uridine Brain Biological Transport General Medicine Molecular biology Rats Thymine Liver chemistry Blood-Brain Barrier Microvessels Female Thymidine |
| Zdroj: | Neurochemical Research. 34:566-573 |
| ISSN: | 1573-6903 0364-3190 |
| Popis: | The brain efflux index (BEI), a measurement of blood-brain barrier (BBB) efflux transport, was estimated at 15 s, 30 s, 1 min, 3 min and 10 min after intracerebral injection of [14C]pyrimidines. An initial steep increase of the BEI values over time was observed for [14]uracil and [14C]thymine, followed by a more moderate increase after 1 min. For the corresponding nucleosides, [14C]uridine and [14C]thymidine, the increase of BEI values over time was less steep and linear between 30 s and 3 min. The apparent BBB efflux clearances for [14C]uridine, [14C]thymidine, [14C]uracil and [14C]thymine were (microl/min/g): 95.2 +/- 12.1, 125.3 +/- 18.4, 290.4 +/- 28 and 358.5 +/- 32.5, respectively, which is at least several folds higher than the predicted BBB influx clearances of uridine, uracil and thymidine. Quick depletion of brain parenchyma from brain microvasculature has revealed that [14C] radioactivity accumulated in brain microvessels after injection of nucleosides [14C]thymidine and [14C]uridine, but that was not observed when nucleobases, [14C]thymine and [14C]uracil, were injected. Reverse transcriptase-PCR revealed that the rat brain and liver (positive control) express dihydropyrimidine dehydrogenase, a key enzyme in pyrimidine nucleobase catabolism. Two bands representing spliced variants have been detected with the relative density of the bands (expressed relative to the density of glyceraldehyde3-phosphate dehydrogenase bands, mean +/- SEM from 3 separate samples) 0.16 +/- 0.06 and 0.04 +/- 0.01 (brain) and 0.49 +/- 0.1 and 0.07 +/- 0.01 (liver). Overall, these results indicate that the net direction of pyrimidine BBB transport is the efflux transport; rapid BBB efflux transport and metabolic breakdown of pyrimidine nucleobases appear to be important for brain homeostasis. |
| Databáze: | OpenAIRE |
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