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Blood-Brain Barrier-Penetrating 6-Halogenopurines Suitable as Pro-Probes for Positron Emission Tomography are Substrates for Human Glutathione Transferases
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
Number of Authors: 2
2016 (English)In: Pharmaceutical Bioprocessing, ISSN 2048-9145, Vol. 4, no 2, 25-30 p.Article in journal (Refereed) Published
Abstract [en]

6-Chloro- and 6-bromopurines can cross the blood-brain barrier and in situ give rise to substrates of multidrug resistance-associated proteins (MRPs). The electrophilic purines form glutathione conjugates in reactions catalyzed by intracellular glutathione transferases (GSTs), and the conjugates are subsequently exported from the cells by ATP-dependent membrane transporters. In rodent model systems it has been demonstrated that suitably radiolabeled 6-halogenopurines by this scheme are pro-probes useful in monitoring the functionality of MRPs in intact brains using positron emission tomography. Prior to applications in human subjects it is imperative to establish the purine pro-probes as effective substrates for human GSTs occurring in brain and other tissues. We have developed a spectrophotometric assay for the glutathione conjugation and determined specific activities with a range of human GSTs as well as some rat GSTs for comparison. The ubiquitous GST P1-1 showed the highest activities with the 6-halogenopurines, which bodes well for the application of pro-probes for human investigations.

Place, publisher, year, edition, pages
2016. Vol. 4, no 2, 25-30 p.
Keyword [en]
Glutathione transferase, 6-Bromopurine, 6-Chloropurine, Blood-brain barrier, Cellular multidrug-resistance probe, Spectrophotometric assay, Glutathione conjugate
National Category
Biological Sciences Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:su:diva-140459ISI: 000392732800001OAI: oai:DiVA.org:su-140459DiVA: diva2:1079504
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2017-03-08Bibliographically approved

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Mannervik, BengtSjödin, Birgitta
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CiteExportLink to record
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