title: Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood-brain barrier: an overview of biology and methodology.
abstract: In the past decade, research into P-glycoprotein involving the blood-brain barrier (BBB) has seen a shift in the concept of the BBB as a structural barrier to that of a functional barrier for xenobiotics and changed simultaneously the strategy for the discovery and development of drugs acting in the CNS. As far as making advances in neurotherapeutics are concerned, the brain-to-blood transport function at the BBB will be one of the most important issues. Knowing the limitations of the in vivo and in vitro methods for BBB efflux research, it is essential to adopt a multidisciplinary approach in investigating the true physiological role of the BBB. Among several methods, the Brain Efflux Index method and the use of conditionally immortalized brain capillary endothelial cell lines, established from transgenic rats harboring temperature-sensitive simian virus 40 large T-antigen gene, are likely to be very useful tools for the BBB efflux transport research. According to our recent findings using these methods, several transporters in the brain capillary endothelial cells appear to play an important role in reducing the brain level of hydrophilic endogenous substrates produced either in the brain or peripheral organs, e.g., neurotransmitters, neuromodulators, metabolites of neurotransmitters, and uremic toxins. It has been reported also that large hydrophilic molecules, such as IgG, apo-transferrin, and amyloid-beta peptide, are susceptible to brain-to-blood efflux transport. In the light of the latest findings, we have formed the hypothesis that the BBB acts as a CNS detoxifying system for both endogenous substrates and xenobiotics in the brain. A fuller understanding of the physiological role of BBB efflux transporters will provide rational insights to assist in the development of safer neurotherapeutics.
authors.affiliation: New Industry Creation Hatchery Center and Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. terasaki@mail.pharm.tohoku.ac.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D014118:Toxins, Biological / Q000378:metabolism; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D014118:Toxins, Biological; D015262:Xenobiotics
references.citation: J Infect Dis. 1988 Sep;158(3):630-2
references.pmid: 2842410
references.citation: J Neurochem. 2003 Nov;87(4):891-901
references.pmid: 14622120
references.citation: Kidney Int. 2004 Jan;65(1):162-74
references.pmid: 14675047
references.citation: Brain Res. 2000 Sep 8;876(1-2):148-53
references.pmid: 10973603
references.citation: J Pharm Pharmacol. 1987 Sep;39(9):705-10
references.pmid: 2445948
references.citation: J Neuropathol Exp Neurol. 1971 Jan;30(1):137-8
references.pmid: 5542523
references.citation: Adv Drug Deliv Rev. 1999 Apr 5;36(2-3):195-209
references.pmid: 10837716
references.citation: Cancer Res. 2004 May 1;64(9):3296-301
references.pmid: 15126373
references.citation: Clin Chim Acta. 1965 Nov;12(5):551-4
references.pmid: 5865891
references.citation: Life Sci. 2000 Oct 20;67(22):2699-711
references.pmid: 11105986
references.citation: Mol Pharmacol. 2002 Jun;61(6):1289-96
references.pmid: 12021389
references.citation: J Pharmacol Exp Ther. 2001 Mar;296(3):723-35
references.pmid: 11181899
references.citation: Int J Cancer. 2002 Feb 10;97(5):626-30
references.pmid: 11807788
references.citation: J Clin Invest. 2000 Dec;106(12):1489-99
references.pmid: 11120756
references.citation: J Neurochem. 2004 Apr;89(2):503-13
references.pmid: 15056293
references.citation: J Biol Chem. 1999 Nov 5;274(45):31891-5
references.pmid: 10542215
references.citation: Science. 1978 Oct 13;202(4364):225-7
references.pmid: 211586
references.citation: Nat Med. 2000 Aug;6(8):916-9
references.pmid: 10932230
references.citation: Acta Physiol Scand. 1980 Mar;108(3):223-9
references.pmid: 6103638
references.citation: Drug Discov Today. 2003 Oct 15;8(20):944-54
references.pmid: 14554158
references.citation: J Neurochem. 2000 Nov;75(5):1907-16
references.pmid: 11032880
references.citation: J Neuroimmunol. 2001 Mar 1;114(1-2):168-72
references.pmid: 11240028
references.citation: J Pharmacol Exp Ther. 2004 Nov;311(2):449-55
references.pmid: 15218051
references.citation: J Neurochem. 2001 Mar;76(5):1597-600
references.pmid: 11238745
references.citation: J Pharmacol Exp Ther. 1996 Jun;277(3):1550-9
references.pmid: 8667222
references.citation: J Neurochem. 2001 Feb;76(4):1121-8
references.pmid: 11181832
references.citation: Life Sci. 1992;51(18):1427-37
references.pmid: 1357522
references.citation: Neuroreport. 2002 Nov 15;13(16):2059-63
references.pmid: 12438926
references.citation: Proc Natl Acad Sci U S A. 1989 Jan;86(2):695-8
references.pmid: 2563168
references.citation: AAPS PharmSci. 2000;2(3):E27
references.pmid: 11741243
references.citation: Pharmacogenetics. 2002 Oct;12(7):535-41
references.pmid: 12360104
references.citation: J Cereb Blood Flow Metab. 2001 Oct;21(10):1232-9
references.pmid: 11598501
references.citation: J Drug Target. 2000;8(6):357-70
references.pmid: 11328662
references.citation: J Neurochem. 2004 Aug;90(4):931-41
references.pmid: 15287899
references.citation: Life Sci. 2000;66(7):649-62
references.pmid: 10794520
references.citation: J Cell Biol. 1967 Jul;34(1):207-17
references.pmid: 6033532
references.citation: J Neurochem. 1992 Apr;58(4):1499-503
references.pmid: 1372345
references.citation: J Neurochem. 1999 May;72(5):2135-44
references.pmid: 10217295
references.citation: Neurosci Res. 2002 Oct;44(2):173-80
references.pmid: 12354632
references.citation: J Pharmacol Exp Ther. 1997 Apr;281(1):369-75
references.pmid: 9103519
references.citation: J Biol Chem. 1995 Jun 23;270(25):14913-8
references.pmid: 7797470
references.citation: Pharm Res. 2003 Sep;20(9):1394-400
references.pmid: 14567633
references.citation: Pharm Res. 2000 Oct;17(10):1198-205
references.pmid: 11145224
references.citation: J Neurochem. 2002 Oct;83(1):57-66
references.pmid: 12358729
references.citation: J Biol Chem. 1986 May 15;261(14):6536-41
references.pmid: 3700406
references.citation: J Cereb Blood Flow Metab. 2003 Apr;23(4):432-40
references.pmid: 12679720
references.citation: J Neurochem. 2004 Aug;90(3):526-36
references.pmid: 15255930
references.citation: J Neurochem. 2001 Oct;79(1):110-8
references.pmid: 11595763
references.citation: J Neurochem. 1999 Sep;73(3):1206-11
references.pmid: 10461913
references.citation: J Histochem Cytochem. 1999 Oct;47(10):1255-64
references.pmid: 10490454
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5
references.pmid: 11438712
references.citation: Cell. 1994 May 20;77(4):491-502
references.pmid: 7910522
references.citation: J Biol Chem. 1999 May 7;274(19):13675-80
references.pmid: 10224140
references.citation: Eur J Pharm Sci. 2001 Jan;12(3):215-22
references.pmid: 11113640