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Drug Metabolism at the Blood–Brain and Blood–CSF Barriers

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Drug Delivery to the Brain

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 10))

Abstract

Drug metabolism is in most cases a detoxification process allowing the organism to inactivate and eliminate foreign substances to which it is exposed. While the liver is the main site of drug metabolism, drug-metabolizing enzymes that catalyze functionalization and conjugation reactions have been detected in the brain, and several of these enzymes are notably enriched at blood–brain interfaces. This chapter summarizes the principles of drug metabolism, reviews the molecular and functional evidence for drug-metabolizing enzyme location at both the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB), and discusses their functional significance for modulating cerebral drug delivery and brain toxin exposure.

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References

  • Abbott NJ (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:629–638

    Article  CAS  PubMed  Google Scholar 

  • Abramovitz M, Homma H, Ishigaki S, Tansey F, Cammer W, Listowsky I (1988) Characterization and localization of glutathione-S-transferases in rat brain and binding of hormones, neurotransmitters, and drugs. J Neurochem 50:50–57

    Article  CAS  PubMed  Google Scholar 

  • Aleksunes LM, Klaassen CD (2012) Coordinated regulation of hepatic phase I and II drug-metabolizing genes and transporters using AhR-, CAR-, PXR-, PPARalpha-, and Nrf2-null mice. Drug Metab Dispos 40:1366–1379

    Article  CAS  PubMed  Google Scholar 

  • Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13

    Article  CAS  PubMed  Google Scholar 

  • Barouki R, Coumoul X, Fernandez-Salguero PM (2007) The aryl hydrocarbon receptor, more than a xenobiotic-interacting protein. FEBS Lett 581:3608–3615

    Article  CAS  PubMed  Google Scholar 

  • Bauer B, Yang X, Hartz AM, Olson ER, Zhao R, Kalvass JC, Pollack GM, Miller DS (2006) In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. Mol Pharmacol 70:1212–1219

    Article  CAS  PubMed  Google Scholar 

  • Bauer B, Hartz AM, Lucking JR, Yang X, Pollack GM, Miller DS (2008) Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi, at the blood-brain barrier. J Cereb Blood Flow Metab 28:1222–1234

    Article  CAS  PubMed  Google Scholar 

  • Beiswanger CM, Diegmann MH, Novak RF, Philbert MA, Graessle TL, Reuhl KR, Lowndes HE (1995) Developmental changes in the cellular distribution of glutathione and glutathione S-transferases in the murine nervous system. Neurotoxicology 16:425–440

    CAS  PubMed  Google Scholar 

  • Benzi G, Berte F, Crema A, Frigo GM (1967) Cerebral drug metabolism investigated by isolated perfused brain in situ. J Pharm Sci 56:1349–1351

    Article  CAS  PubMed  Google Scholar 

  • Betz AL, Firth JA, Goldstein GW (1980) Polarity of the blood-brain barrier: distribution of enzymes between the luminal and antiluminal membranes of brain capillary endothelial cells. Brain Res 192:17–28

    Article  CAS  PubMed  Google Scholar 

  • Bhamre S, Bhagwat SV, Shankar SK, Williams DE, Ravindranath V (1993) Cerebral flavin-containing monooxygenase-mediated metabolism of antidepressants in brain: immunochemical properties and immunocytochemical localization. J Pharmacol Exp Ther 267:555–559

    CAS  PubMed  Google Scholar 

  • Brittebo EB (1994) Metabolism-dependent binding of the heterocyclic amine Trp-P-1 in endothelial cells of choroid plexus and in large cerebral veins of cytochrome P450-induced mice. Brain Res 659:91–98

    Article  CAS  PubMed  Google Scholar 

  • Brown PD, Davies SL, Speake T, Millar ID (2004) Molecular mechanisms of cerebrospinal fluid production. Neuroscience 129:957–970

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Burdo J, Dargusch R, Schubert D (2006) Distribution of the cystine/glutamate antiporter system xc- in the brain, kidney, and duodenum. J Histochem Cytochem 54:549–557

    Article  CAS  PubMed  Google Scholar 

  • Calabria AR, Shusta EV (2008) A genomic comparison of in vivo and in vitro brain microvascular endothelial cells. J Cereb Blood Flow Metab 28:135–148

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Calkins MJ et al (2009) The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 11:497–508

    Article  CAS  PubMed  Google Scholar 

  • Cammer W, Tansey F, Abramovitz M, Ishigaki S, Listowsky I (1989) Differential localization of glutathione-S-transferase Yp and Yb subunits in oligodendrocytes and astrocytes of rat brain. J Neurochem 52:876–883

    Article  CAS  PubMed  Google Scholar 

  • Carder PJ, Hume R, Fryer AA, Strange RC, Lauder J, Bell JE (1990) Glutathione S-transferase in human brain. Neuropathol Appl Neurobiol 16:293–303

    Article  CAS  PubMed  Google Scholar 

  • Cardoso FL, Brites D, Brito MA (2010) Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev 64:328–363

    Article  CAS  PubMed  Google Scholar 

  • Cashman JR (2000) Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism. Curr Drug Metab 1:181–191

    Article  CAS  PubMed  Google Scholar 

  • Chan GN, Hoque MT, Cummins CL, Bendayan R (2010) Regulation of P-glycoprotein by orphan nuclear receptors in human brain microvessel endothelial cells. J Neurochem 118:163–175

    Article  CAS  Google Scholar 

  • Chodobski A, Szmydynger-Chodobska J (2001) Choroid plexus: target for polypeptides and site of their synthesis. Microsc Res Tech 52:65–82

    Article  CAS  PubMed  Google Scholar 

  • Choi YK, Kim KW (2008) Blood-neural barrier: its diversity and coordinated cell-to-cell communication. BMB Rep 41:345–352

    Article  CAS  PubMed  Google Scholar 

  • Christrup LL (1997) Morphine metabolites. Acta Anaesthesiol Scand 41:116–122

    Article  CAS  PubMed  Google Scholar 

  • Damkier HH, Brown PD, Praetorius J (2010) Epithelial pathways in choroid plexus electrolyte transport. Physiology (Bethesda) 25:239–249

    Article  CAS  Google Scholar 

  • Dauchy S, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C, Couraud PO, Scherrmann JM, De Waziers I, Decleves X (2008) ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier. J Neurochem 107:1518–1528

    Article  CAS  PubMed  Google Scholar 

  • Dauchy S, Miller F, Couraud PO, Weaver RJ, Weksler B, Romero IA, Scherrmann JM, De Waziers I, Decleves X (2009) Expression and transcriptional regulation of ABC transporters and cytochromes P450 in hCMEC/D3 human cerebral microvascular endothelial cells. Biochem Pharmacol 77:897–909

    Article  CAS  PubMed  Google Scholar 

  • de Boer AG, Gaillard PJ (2006) Blood-brain barrier dysfunction and recovery. J Neural Transm 113:455–462

    Article  PubMed  Google Scholar 

  • Decleves X, Jacob A, Yousif S, Shawahna R, Potin S, Scherrmann JM (2011) Interplay of drug metabolizing CYP450 enzymes and ABC transporters in the blood-brain barrier. Curr Drug Metab 12:732–741

    Article  CAS  PubMed  Google Scholar 

  • Denison MS, Nagy SR (2003) Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol Toxicol 43:309–334

    Article  CAS  PubMed  Google Scholar 

  • Dey A, Jones JE, Nebert DW (1999) Tissue- and cell type-specific expression of cytochrome P450 1A1 and cytochrome P450 1A2 mRNA in the mouse localized in situ hybridization. Biochem Pharmacol 58:525–537

    Article  CAS  PubMed  Google Scholar 

  • Duffel MW, Marshal AD, McPhie P, Sharma V, Jakoby WB (2001) Enzymatic aspects of the phenol (aryl) sulfotransferases. Drug Metab Rev 33:369–395

    Article  CAS  PubMed  Google Scholar 

  • Dutheil F, Beaune P, Loriot MA (2008) Xenobiotic metabolizing enzymes in the central nervous system: contribution of cytochrome P450 enzymes in normal and pathological human brain. Biochimie 90:426–436

    Article  CAS  PubMed  Google Scholar 

  • Dziegielewska KM, Ek J, Habgood MD, Saunders NR (2001) Development of the choroid plexus. Microsc Res Tech 52:5–20

    Article  CAS  PubMed  Google Scholar 

  • Eaton DL, Bammler TK (1999) Concise review of the glutathione S-transferases and their significance to toxicology. Toxicol Sci 49:56–164

    Article  Google Scholar 

  • Ek CJ, Dziegielewska KM, Stolp H, Saunders NR (2006) Functional effectiveness of the blood-brain barrier to small water-soluble molecules in developing and adult opossum (Monodelphis domestica). J Comp Neurol 496:13–26

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ek CJ, Dziegielewska KM, Habgood MD, Saunders NR (2012) Barriers in the developing brain and neurotoxicology. Neurotoxicology 33:586–604

    Article  CAS  PubMed  Google Scholar 

  • Engelhardt B, Ransohoff RM (2005) The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26:485–495

    Article  CAS  PubMed  Google Scholar 

  • Gamage N, Barnett A, Hempel N, Duggleby RG, Windmill KF, Martin JL, McManus ME (2006) Human sulfotransferases and their role in chemical metabolism. Toxicol Sci 90:5–22

    Article  CAS  PubMed  Google Scholar 

  • Gazzin S, Strazielle N, Schmitt C, Fevre-Montange M, Ostrow JD, Tiribelli C, Ghersi-Egea JF (2008) Differential expression of the multidrug resistance-related proteins ABCb1 and ABCc1 between blood-brain interfaces. J Comp Neurol 510:497–507

    Article  CAS  PubMed  Google Scholar 

  • Gazzin S, Strazielle N, Tiribelli C, Ghersi-Egea JF (2012) Transport and metabolism at blood-brain interfaces and in neural cells: relevance to bilirubin-induced encephalopathy. Front Pharmacol 3:89

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gelhaus SL, Harvey RG, Penning TM, Blair IA (2011) Regulation of benzo[a]pyrene-mediated DNA- and glutathione-adduct formation by 2,3,7,8-tetrachlorodibenzo-p-dioxin in human lung cells. Chem Res Toxicol 24:89–98

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ghersi-Egea JF, Minn A, Siest G (1988) A new aspect of the protective functions of the blood-brain barrier: activities of four drug-metabolizing enzymes in isolated rat brain microvessels. Life Sci 42:2515–2523

    Article  CAS  PubMed  Google Scholar 

  • Ghersi-Egea JF, Perrin R, Leininger-Muller B, Grassiot MC, Jeandel C, Floquet J, Cuny G, Siest G, Minn A (1993) Subcellular localization of cytochrome P450, and activities of several enzymes responsible for drug metabolism in the human brain. Biochem Pharmacol 45:647–658

    Article  CAS  PubMed  Google Scholar 

  • Ghersi-Egea JF, Leninger-Muller B, Suleman G, Siest G, Minn A (1994) Localization of drug-metabolizing enzyme activities to blood-brain interfaces and circumventricular organs. J Neurochem 62:1089–1096

    Article  CAS  PubMed  Google Scholar 

  • Ghersi-Egea JF, Leininger-Muller B, Cecchelli R, Fenstermacher JD (1995) Blood-brain interfaces: relevance to cerebral drug metabolism. Toxicol Lett 82–83:645–653

    Article  PubMed  Google Scholar 

  • Ghersi-Egea JF, Maupoil V, Ray D, Rochette L (1998) Electronic spin resonance detection of superoxide and hydroxyl radicals during the reductive metabolism of drugs by rat brain preparations and isolated cerebral microvessels. Free Radic Biol Med 24:1074–1081

    Article  CAS  PubMed  Google Scholar 

  • Ghersi-Egea JF, Strazielle N, Murat A, Jouvet A, Buenerd A, Belin MF (2006) Brain protection at the blood-cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism. J Cereb Blood Flow Metab 4:4

    Google Scholar 

  • Ghersi-Egea JF, Gazzin S, Strazielle N (2009a) Blood-brain interfaces and bilirubin-induced neurological diseases. Curr Pharm Des 15:2893–2907

    Article  CAS  PubMed  Google Scholar 

  • Ghersi-Egea JF, Monkkonen KS, Schmitt C, Honnorat J, Fevre-Montange M, Strazielle N (2009b) Blood-brain interfaces and cerebral drug bioavailability. Rev Neurol (Paris) 165:1029–1038

    Article  Google Scholar 

  • Ghosh C, Gonzalez-Martinez J, Hossain M, Cucullo L, Fazio V, Janigro D, Marchi N (2010) Pattern of P450 expression at the human blood-brain barrier: roles of epileptic condition and laminar flow. Epilepsia 51:1408–1417

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ginguene C, Champier J, Maallem S, Strazielle N, Jouvet A, Fevre-Montange M, Ghersi-Egea JF (2010) P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) localize in the microvessels forming the blood-tumor barrier in ependymomas. Brain Pathol 20:926–935

    CAS  PubMed  Google Scholar 

  • Gottwald MD, Bainbridge JL, Dowling GA, Aminoff MJ, Alldredge BK (1997) New pharmacotherapy for Parkinson’s disease. Ann Pharmacother 31:1205–1217

    CAS  PubMed  Google Scholar 

  • Granberg L, Ostergren A, Brandt I, Brittebo EB (2003) CYP1A1 and CYP1B1 in blood-brain interfaces: CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells. Drug Metab Dispos 31:259–265

    Article  CAS  PubMed  Google Scholar 

  • Hansson T, Tindberg N, Ingelman-Sundberg M, Kohler C (1990) Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system. Neuroscience 34:451–463

    Article  CAS  PubMed  Google Scholar 

  • Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185

    Article  CAS  PubMed  Google Scholar 

  • Hawkins BT, Egleton RD (2006) Fluorescence imaging of blood-brain barrier disruption. J Neurosci Methods 151:262–267

    Article  CAS  PubMed  Google Scholar 

  • Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88

    Article  CAS  PubMed  Google Scholar 

  • Ishikawa T (1992) The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci 17:463–468

    Article  CAS  PubMed  Google Scholar 

  • Jacob A, Hartz AM, Potin S, Coumoul X, Yousif S, Scherrmann JM, Bauer B, Decleves X (2011) Aryl hydrocarbon receptor-dependent upregulation of Cyp1b1 by TCDD and diesel exhaust particles in rat brain microvessels. Fluids Barriers CNS 8:23

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Janmohamed A, Hernandez D, Phillips IR, Shephard EA (2004) Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos). Biochem Pharmacol 68:73–83

    Article  CAS  PubMed  Google Scholar 

  • Johansson PA, Dziegielewska KM, Liddelow SA, Saunders NR (2008) The blood-CSF barrier explained: when development is not immaturity. Bioessays 30:237–248

    Article  CAS  PubMed  Google Scholar 

  • Johnson JA, el Barbary A, Kornguth SE, Brugge JF, Siegel FL (1993) Glutathione S-transferase isoenzymes in rat brain neurons and glia. J Neurosci 13:2013–2023

    CAS  PubMed  Google Scholar 

  • Josserand V, Pelerin H, de Bruin B, Jego B, Kuhnast B, Hinnen F, Duconge F, Boisgard R, Beuvon F, Chassoux F, Daumas-Duport C, Ezan E, Dolle F, Mabondzo A, Tavitian B (2006) Evaluation of drug penetration into the brain: a double study by in vivo imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier. J Pharmacol Exp Ther 316:79–86

    Article  CAS  PubMed  Google Scholar 

  • Karhunen T, Tilgmann C, Ulmanen I, Panula P (1995) Neuronal and non-neuronal catechol-O-methyltransferase in primary cultures of rat brain cells. Int J Dev Neurosci 13:825–834

    Article  CAS  PubMed  Google Scholar 

  • Karlgren M, Backlund M, Johansson I, Oscarson M, Ingelman-Sundberg M (2004) Characterization and tissue distribution of a novel human cytochrome P450-CYP2U1. Biochem Biophys Res Commun 315:679–685

    Article  CAS  PubMed  Google Scholar 

  • Keep RF, Jones HC (1990) A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries and ventricular ependyma in the rat. Brain Res Dev Brain Res 56:47–53

    Article  CAS  PubMed  Google Scholar 

  • Khan E (2005) An examination of the blood-brain barrier in health and disease. Br J Nurs 14:509–513

    PubMed  Google Scholar 

  • King CD, Rios GR, Green MD, Tephly TR (2000) UDPglucuronosyltransferases. Curr Drug Metab 1:143–161

    Article  CAS  PubMed  Google Scholar 

  • Kratzer I, Vasiljevic A, Rey C, Fevre-Montange M, Saunders N, Strazielle N, Ghersi-Egea JF (2012) Complexity and developmental changes in the expression pattern of claudins at the blood-CSF barrier. Histochem Cell Biol 138:861–879

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kusuhara H, Sugiyama Y (2004) Efflux transport systems for organic anions and cations at the blood-CSF barrier. Adv Drug Deliv Rev 56:1741–1763

    Article  CAS  PubMed  Google Scholar 

  • Lee SW, Kim WJ, Park JA, Choi YK, Kwon YW, Kim KW (2006) Blood-brain barrier interfaces and brain tumors. Arch Pharm Res 29:265–275

    Article  CAS  PubMed  Google Scholar 

  • Lee A, Anderson AR, Rayfield AJ, Stevens MG, Poronnik P, Meabon JS, Cook DG, Pow DV (2012) Localisation of novel forms of glutamate transporters and the cystine-glutamate antiporter in the choroid plexus: Implications for CSF glutamate homeostasis. J Chem Neuroanat 43:64–75

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, Mercer KE, Zhuang Y, Panetta JC, Johnston B, Scheper RJ, Stewart CF, Schuetz JD (2004) Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol 24:7612–7621

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Leininger-Muller B, Ghersi-Egea JF, Siest G, Minn A (1994) Induction and immunological characterization of the uridine diphosphate-glucuronosyltransferase conjugating 1-naphthol in the rat choroid plexus. Neurosci Lett 175:37–40

    Article  CAS  PubMed  Google Scholar 

  • Leslie EM, Deeley RG, Cole SP (2005) Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204:216–237

    Article  CAS  PubMed  Google Scholar 

  • Liang T, Habegger K, Spence JP, Foroud T, Ellison JA, Lumeng L, Li TK, Carr LG (2004) Glutathione S-transferase 8-8 expression is lower in alcohol-preferring than in alcohol-nonpreferring rats. Alcohol Clin Exp Res 28:1622–1628

    Article  CAS  PubMed  Google Scholar 

  • Listowsky I, Rowe JD, Patskovsky YV, Tchaikovskaya T, Shintani N, Novikova E, Nieves E (1998) Human testicular glutathione S-transferases: insights into tissue-specific expression of the diverse subunit classes. Chem Biol Interact 111–112:103–112

    Article  PubMed  Google Scholar 

  • Liu S, Stoesz SP, Pickett CB (1998) Identification of a novel human glutathione S-transferase using bioinformatics. Arch Biochem Biophys 352:306–313

    Article  CAS  PubMed  Google Scholar 

  • Marowsky A, Burgener J, Falck JR, Fritschy JM, Arand M (2009) Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism. Neuroscience 163:646–661

    Article  CAS  PubMed  Google Scholar 

  • McLeod HL, Krynetski EY, Relling MV, Evans WE (2000) Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14:567–572

    Article  CAS  PubMed  Google Scholar 

  • Miksys SL, Tyndale RF (2002) Drug-metabolizing cytochrome P450s in the brain. J Psychiatry Neurosci 27:406–415

    PubMed Central  PubMed  Google Scholar 

  • Miksys S, Hoffmann E, Tyndale RF (2000a) Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment. Biochem Pharmacol 59:1501–1511

    Article  CAS  PubMed  Google Scholar 

  • Miksys S, Rao Y, Sellers EM, Kwan M, Mendis D, Tyndale RF (2000b) Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica 30:547–564

    Article  CAS  PubMed  Google Scholar 

  • Minn A, Ghersi-Egea JF, Perrin R, Leininger B, Siest G (1991) Drug metabolizing enzymes in the brain and cerebral microvessels. Brain Res Brain Res Rev 16:65–82

    Article  CAS  PubMed  Google Scholar 

  • Monks TJ, Ghersi-Egea JF, Philbert M, Cooper AJ, Lock EA (1999) Symposium overview: the role of glutathione in neuroprotection and neurotoxicity. Toxicol Sci 51:161–177

    Article  CAS  PubMed  Google Scholar 

  • Morse DC, Stein AP, Thomas PE, Lowndes HE (1998) Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain. Toxicol Appl Pharmacol 152:232–239

    Article  CAS  PubMed  Google Scholar 

  • Nebert DW, Russell DW (2002) Clinical importance of the cytochromes P450. Lancet 360:1155–1162

    Article  CAS  PubMed  Google Scholar 

  • Nishibori M, Tahara A, Sawada K, Sakiyama J, Nakaya N, Saeki K (2000) Neuronal and vascular localization of histamine N-methyltransferase in the bovine central nervous system. Eur J Neurosci 12:415–424

    Article  CAS  PubMed  Google Scholar 

  • Ott M, Fricker G, Bauer B (2009) Pregnane X receptor (PXR) regulates P-glycoprotein at the blood-brain barrier: functional similarities between pig and human PXR. J Pharmacol Exp Ther 329:141–149

    Article  CAS  PubMed  Google Scholar 

  • Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood-brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1:223–236

    Article  PubMed  Google Scholar 

  • Philbert MA, Beiswanger CM, Manson MM, Green JA, Novak RF, Primiano T, Reuhl KR, Lowndes HE (1995) Glutathione S-transferases and gamma-glutamyl transpeptidase in the rat nervous systems: a basis for differential susceptibility to neurotoxicants. Neurotoxicology 16:349–362

    CAS  PubMed  Google Scholar 

  • Redzic ZB, Preston JE, Duncan JA, Chodobski A, Szmydynger-Chodobska J (2005) The choroid plexus-cerebrospinal fluid system: from development to aging. Curr Top Dev Biol 71:1–52

    Article  CAS  PubMed  Google Scholar 

  • Riachi NJ, Harik SI (1988) Strain differences in systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in mice correlate best with monoamine oxidase activity at the blood-brain barrier. Life Sci 42:2359–2363

    Article  CAS  PubMed  Google Scholar 

  • Riachi NJ, Harik SI, Kalaria RN, Sayre LM (1988) On the mechanisms underlying 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. II. Susceptibility among mammalian species correlates with the toxin’s metabolic patterns in brain microvessels and liver. J Pharmacol Exp Ther 244:443–448

    CAS  PubMed  Google Scholar 

  • Richard K, Hume R, Kaptein E, Stanley EL, Visser TJ, Coughtrie MW (2001) Sulfation of thyroid hormone and dopamine during human development: ontogeny of phenol sulfotransferases and arylsulfatase in liver, lung, and brain. J Clin Endocrinol Metab 86:2734–2742

    CAS  PubMed  Google Scholar 

  • Rivett AJ, Eddy BJ, Roth JA (1982) Contribution of sulfate conjugation, deamination, and O-methylation to metabolism of dopamine and norepinephrine in human brain. J Neurochem 39:1009–1016

    Article  CAS  PubMed  Google Scholar 

  • Schmitt C, Strazielle N, Richaud P, Bouron A, Ghersi-Egea JF (2011) Active transport at the blood-CSF barrier contributes to manganese influx into the brain. J Neurochem 117:747–756

    CAS  PubMed  Google Scholar 

  • Schreiber G, Richardson SJ (1997) The evolution of gene expression, structure and function of transthyretin. Comp Biochem Physiol B Biochem Mol Biol 116:137–160

    Article  CAS  PubMed  Google Scholar 

  • Shang W, Liu WH, Zhao XH, Sun QJ, Bi JZ, Chi ZF (2008) Expressions of glutathione S-transferase alpha, mu, and pi in brains of medically intractable epileptic patients. BMC Neurosci 9:67

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Shawahna R, Uchida Y, Decleves X, Ohtsuki S, Yousif S, Dauchy S, Jacob A, Chassoux F, Daumas-Duport C, Couraud PO, Terasaki T, Scherrmann JM (2011) Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm 8(4):1332–1341

    Article  CAS  PubMed  Google Scholar 

  • Stanulla M, Schaeffeler E, Moricke A, Coulthard SA, Cario G, Schrauder A, Kaatsch P, Dordelmann M, Welte K, Zimmermann M, Reiter A, Eichelbaum M, Riehm H, Schrappe M, Schwab M (2009) Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Munster protocols. Blood 114:1314–1318

    Article  CAS  PubMed  Google Scholar 

  • Strazielle N, Ghersi-Egea JF (1997) Drug metabolism in newborn rat choroid plexus from lateral, third and fourth ventricle. Dev Anim Vet Sci 27:895–901

    Google Scholar 

  • Strazielle N, Ghersi-Egea JF (1999) Demonstration of a coupled metabolism-efflux process at the choroid plexus as a mechanism of brain protection toward xenobiotics. J Neurosci 19:6275–6289

    CAS  PubMed  Google Scholar 

  • Strazielle N, Ghersi-Egea JF (2000a) Choroid plexus in the central nervous system: biology and physiopathology. J Neuropathol Exp Neurol 59:561–574

    CAS  PubMed  Google Scholar 

  • Strazielle N, Ghersi-Egea JF (2000b) Implication of blood-brain interfaces in cerebral drug metabolism and drug metabolite disposition. In: Williams G, Aruoma OI (eds) Molecular drug metabolism and toxicology. OICA International, Saint Lucia, London, pp 181–200

    Google Scholar 

  • Strazielle N, Ghersi-Egea JF (2005) Factors affecting delivery of antiviral drugs to the brain. Rev Med Virol 15:105–133

    Article  CAS  PubMed  Google Scholar 

  • Strazielle N, Belin MF, Ghersi-Egea JF (2003) Choroid plexus controls brain availability of anti-HIV nucleoside analogs via pharmacologically inhibitable organic anion transporters. AIDS 17:1473–1485

    CAS  PubMed  Google Scholar 

  • Strazielle N, Khuth ST, Ghersi-Egea JF (2004) Detoxification systems, passive and specific transport for drugs at the blood-CSF barrier in normal and pathological situations. Adv Drug Deliv Rev 56:1717–1740

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Shih AY, Johannssen HC, Erb H, Li P, Murphy TH (2006) Two-photon imaging of glutathione levels in intact brain indicates enhanced redox buffering in developing neurons and cells at the cerebrospinal fluid and blood-brain interface. J Biol Chem 281:17420–17431

    Article  CAS  PubMed  Google Scholar 

  • Sura P, Sura R, Enayetallah AE, Grant DF (2008) Distribution and expression of soluble epoxide hydrolase in human brain. J Histochem Cytochem 56:551–559

    Article  CAS  PubMed  Google Scholar 

  • Synold TW, Dussault I, Forman BM (2001) The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 7:584–590

    Article  CAS  PubMed  Google Scholar 

  • Szmydynger-Chodobska J, Strazielle N, Zink BJ, Ghersi-Egea JF, Chodobski A (2009) The role of the choroid plexus in neutrophil invasion after traumatic brain injury. J Cereb Blood Flow Metab 29:1503–1516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tate SS, Ross LL, Meister A (1973) The -glutamyl cycle in the choroid plexus: its possible function in amino acid transport. Proc Natl Acad Sci U S A 70:1447–1449

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tayarani I, Cloez I, Clement M, Bourre JM (1989) Antioxidant enzymes and related trace elements in aging brain capillaries and choroid plexus. J Neurochem 53:817–824

    Article  CAS  PubMed  Google Scholar 

  • Teissier E, Fennrich S, Strazielle N, Daval JL, Ray D, Schlosshauer B, Ghersi-Egea JF (1998) Drug metabolism in in vitro organotypic and cellular models of mammalian central nervous system: activities of membrane-bound epoxide hydrolase and NADPH-cytochrome P-450 (c) reductase. Neurotoxicology 19:347–355

    CAS  PubMed  Google Scholar 

  • Tolson A, Wang H (2010) Regulation of drug-metabolizing enzymes by xenobiotics receptors: PXR and CAR. Adv Drug Deliv Rev 62:1238–1249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Van Gelder NM (1968) A possible enzyme barrier for gamma-aminobutyric acid in the central nervous system. Prog Brain Res 29:259–271

    Article  PubMed  Google Scholar 

  • Vasiliou V, Gonzalez FJ (2008) Role of CYP1B1 in glaucoma. Annu Rev Pharmacol Toxicol 48:333–358

    Article  CAS  PubMed  Google Scholar 

  • Vidal JD, VandeVoort CA, Marcus CB, Lazarewicz NR, Conley AJ (2006) In vitro exposure to environmental tobacco smoke induces CYP1B1 expression in human luteinized granulosa cells. Reprod Toxicol 22:731–737

    Article  CAS  PubMed  Google Scholar 

  • Volk B, Hettmannsperger U, Papp T, Amelizad Z, Oesch F, Knoth R (1991) Mapping of phenytoin-inducible cytochrome P450 immunoreactivity in the mouse central nervous system. Neuroscience 42:215–235

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Sykes DB, Miller DS (2010) Constitutive androstane receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. Mol Pharmacol 78:376–383

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Hawkins BT, Miller DS (2011) Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. FASEB J 25:644–652

    Article  CAS  PubMed  Google Scholar 

  • Wijnholds J, deLange EC, Scheffer GL, van den Berg DJ, Mol CA, van der Valk M, Schinkel AH, Scheper RJ, Breimer DD, Borst P (2000) Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest 105:279–285

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu C, Li CY, Kong AN (2005) Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res 28:249–268

    Article  CAS  PubMed  Google Scholar 

  • Zastre JA, Chan GN, Ronaldson PT, Ramaswamy M, Couraud PO, Romero IA, Weksler B, Bendayan M, Bendayan R (2009) Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. J Neurosci Res 87:1023–1036

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, Harder DR (2002) Cerebral capillary endothelial cell mitogenesis and morphogenesis induced by astrocytic epoxyeicosatrienoic acid. Stroke 33:2957–2964

    Article  CAS  PubMed  Google Scholar 

  • Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

This work was supported by the European Union (HEALTH- F2-2009-241778) to Nathalie Strazielle and Jean-François Ghersi-Egea.

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Authors and Affiliations

  1. INSERM, U705, CNRS UMR 8206, Universités Paris Descartes et Didero, Paris, France

    Xavier Declèves & Jean-Michel Scherrmann

  2. Brain-i, Lyon, France

    Nathalie Strazielle

  3. Inserm U1028, CNRS UMR 5292, Lyon Neuroscience Research Center, Lyon-1 University, Lyon, France

    Jean-François Ghersi-Egea

Authors
  1. Xavier Declèves
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  2. Nathalie Strazielle
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  3. Jean-Michel Scherrmann
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  4. Jean-François Ghersi-Egea
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Corresponding author

Correspondence to Jean-François Ghersi-Egea .

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Editors and Affiliations

  1. Pharmaceutical Biosciences, Uppsala University Pharmacokinetics and Drug Therapy, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

  2. LACDR/Pharmacology, Leiden University, Leiden, The Netherlands

    Elizabeth C.M. de Lange

  3. Pharmaceutical Sciences Division, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA

    Robert G. Thorne

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Declèves, X., Strazielle, N., Scherrmann, JM., Ghersi-Egea, JF. (2014). Drug Metabolism at the Blood–Brain and Blood–CSF Barriers. In: Hammarlund-Udenaes, M., de Lange, E., Thorne, R. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9105-7_4

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