Blood-brain barrier P450 enzymes and multidrug transporters in drug resistance: A synergistic role in neurological diseases

Current Drug Metabolism

Volumn 12, Issue 8, 2011, Pages 742-749

  Ghosh, Chaitali ^a   Puvenna, Vikram ^a   Gonzalez Martinez, Jorge ^a   Janigro, Damir ^a   Marchi, Nicola ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

Author keywords

Blood brain barrier; Drug resistant epilepsy; Multidrug transporters proteins (MDT); P450 enzymes

Indexed keywords

ACYLTRANSFERASE; ANTICONVULSIVE AGENT; BREAST CANCER RESISTANCE PROTEIN; CARBAMAZEPINE; CYTOCHROME P450; CYTOCHROME P450 1A1; CYTOCHROME P450 1A2; CYTOCHROME P450 1B1; CYTOCHROME P450 2A6; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 2E1; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; CYTOCHROME P450 46A1; EPOXIDE HYDROLASE; ETIRACETAM; GLUCURONOSYLTRANSFERASE; GLUTATHIONE TRANSFERASE; GLYCOPROTEIN P; LAMOTRIGINE; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 2; OXCARBAZEPINE; PHENOBARBITAL; PHENYTOIN; PREGNANE X RECEPTOR; TOPIRAMATE; UNCLASSIFIED DRUG; VALPROIC ACID;

ALZHEIMER DISEASE; BLOOD BRAIN BARRIER; BRAIN CELL; CELL SURVIVAL; CENTRAL NERVOUS SYSTEM DISEASE; CREUTZFELDT JAKOB DISEASE; DRUG DISTRIBUTION; DRUG METABOLISM; DRUG TRANSFORMATION; EPILEPSY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NEUROLOGIC DISEASE; NONHUMAN; PARKINSON DISEASE; PROTEIN EXPRESSION; REVIEW;

EID: 80053496670     PISSN: 13892002     EISSN: 18755453     Source Type: Journal    
DOI: 10.2174/138920011798357051     Document Type: Review

References (120)

1. Abbott, N. J. Dynamics of CNS barriers: evolution, differentiation,and modulation. Cell Mol. Neurobiol., 2005, 25(1), 5-23. (Pubitemid 40558582)
2. Abbott, N. J.; Ronnback, L.; Hansson, E. Astrocyte- endothelialinteractions at the blood-brain barrier. Nat. Rev. Neurosci., 2006,7(1), 41-53.
3. Abbott, N. J.; Dolman, D. E.; Patabendige, A. K. Assays to predictdrug permeation across the blood-brain barrier, and distribution tobrain. Curr. Drug Metab., 2008, 9(9), 901-910.
4. Abbott, N. J.; Patabendige, A. A.; Dolman, D. E.; Yusof, S. R.;Begley, D. J. Structure and function of the blood-brain barrier.Neurobiol. Dis., 2010, 37(1), 13-25.
5. Pardridge, W. M. Blood-brain barrier delivery. Drug Discov.Today, 2007, 12(1-2), 54-61. (Pubitemid 46014479)
6. Ballabh, P.; Braun, A.; Nedergaard, M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol.Dis., 2004, 16(1), 1-13. (Pubitemid 38569790)
7. Kwan, P.; Arzimanoglou, A.; Berg, A. T.; Brodie, M. J.; Allen, H.W.; Mathern, G.; Moshe, S. L.; Perucca, E.; Wiebe, S.; French, J.Definition of drug resistant epilepsy: consensus proposal by the adhoc Task Force of the ILAE Commission on Therapeutic Strategies.Epilepsia, 2010, 51(6), 1069-1077.
8. Granata, T.; Marchi, N.; Carlton, E.; Ghosh, C.; Gonzalez-Martinez, J.; Alexopoulos, A. V.; Janigro, D. Management of thepatient with medically refractory epilepsy. Expert Rev. Neurother.,2009, 9(12), 1791-1802.
9. Perucca, E.; French, J.; Bialer, M. Development of new antiepilepticdrugs: challenges, incentives, and recent advances. LancetNeurol., 2007, 6(9), 793-804. (Pubitemid 47243712)
10. Beck, H. Plasticity of antiepileptic drug targets. Epilepsia, 2007,48 Suppl 1 14-18. (Pubitemid 46280514)
11. Loscher, W.; Sills, G. J. Drug resistance in epilepsy: why is asimple explanation not enough? Epilepsia, 2007, 48(12), 2370-2372. (Pubitemid 350243408)
12. Remy, S.; Gabriel, S.; Urban, B. W.; Dietrich, D.; Lehmann, T. N.;Elger, C. E.; Heinemann, U.; Beck, H. A novel mechanism underlyingdrug resistance in chronic epilepsy. Ann. Neurol., 2003,53(4), 469-479. (Pubitemid 36373258)
13. Remy, S.; Urban, B. W.; Elger, C. E.; Beck, H. Anticonvulsantpharmacology of voltage-gated Na+ channels in hippocampal neuronsof control and chronically epileptic rats. Eur. J. Neurosci.,2003, 17(12), 2648-2658. (Pubitemid 36819290)
14. Dombrowski, S. M.; Desai, S. Y.; Marroni, M.; Cucullo, L.; Goodrich,K.; Bingaman, W.; Mayberg, M. R.; Bengez, L.; Janigro, D.Overexpression of multiple drug resistance genes in endothelialcells from patients with refractory epilepsy. Epilepsia, 2001,42(12), 1501-1506. (Pubitemid 34020086)
15. Loscher, W.; Potschka, H. Drug resistance in brain diseases andthe role of drug efflux transporters. Nat. Rev. Neurosci., 2005, 6(8),591-602. (Pubitemid 41059334)
16. Loscher, W.; Potschka, H. Role of drug efflux transporters in thebrain for drug disposition and treatment of brain diseases. Prog.Neurobiol., 2005, 76(1), 22-76. (Pubitemid 41033402)
17. Marchi, N.; Hallene, K. L.; Kight, K. M.; Cucullo, L.; Moddel, G.;Bingaman, W.; Dini, G.; Vezzani, A.; Janigro, D. Significance ofMDR1 and multiple drug resistance in refractory human epilepticbrain. BMC Med., 2004, 2 37.
18. Sisodiya, S. M.; Goldstein, D. B. Drug resistance in epilepsy: moretwists in the tale. Epilepsia, 2007, 48(12), 2369-2370. (Pubitemid 350243407)
19. Marchi, N.; Gonzalez-Martinez, J.; Nguyen, M. T.; Granata, T.;Janigro, D. Transporters in drug-refractory epilepsy: clinical significance.Clin. Pharmacol. Ther., 2010, 87(1), 13-15.
20. Potschka, H.; Fedrowitz, M.; Loscher, W. P-Glycoproteinmediatedefflux of phenobarbital, lamotrigine, and felbamate at theblood-brain barrier: evidence from microdialysis experiments inrats. Neurosci. Lett., 2002, 327(3), 173-176.
21. Potschka, H.; Baltes, S.; Loscher, W. Inhibition of multidrugtransporters by verapamil or probenecid does not alter blood-brainbarrier penetration of levetiracetam in rats. Epilepsy Res., 2004,58(2-3), 85-91. (Pubitemid 38553945)
22. Marchi, N.; Guiso, G.; Rizzi, M.; Pirker, S.; Novak, K.; Czech, T.;Baumgartner, C.; Janigro, D.; Caccia, S.; Vezzani, A. A pilot studyon brain-to-plasma partition of 10,11-dyhydro-10-hydroxy-5Hdibenzo(b,f)azepine-5- carboxamide and MDR1 brain expression inepilepsy patients not responding to oxcarbazepine. Epilepsia, 2005,46(10), 1613-1619.
23. Ghosh, C.; Gonzalez-Martinez, J.; Hossain, M.; Cucullo, L.; Fazio,V.; Janigro, D.; Marchi, N. Pattern of P450 expression at the humanblood-brain barrier: roles of epileptic condition and laminarflow. Epilepsia, 2010, 51(8), 1408-1417.
24. Ghosh, C.; Marchi, N.; Desai, N. K.; Puvenna, V.; Hossain, M.;Gonzalez-Martinez, J.; Alexopoulos, A. V.; Janigro, D. Cellularlocalization and functional significance of CYP3A4 in the humanepileptic brain. Epilepsia, 2011, 52(3), 562-571.
25. Dutheil, F.; Beaune, P.; Loriot, M. A. Xenobiotic metabolizingenzymes in the central nervous system: Contribution of cytochromeP450 enzymes in normal and pathological human brain. Biochimie,2008, 90(3), 426-436.
26. Pearce, R. E.; Lu, W.; Wang, Y.; Uetrecht, J. P.; Correia, M. A.;Leeder, J. S. Pathways of carbamazepine bioactivation in vitro. III.The role of human cytochrome P450 enzymes in the formation of2,3-dihydroxycarbamazepine. Drug Metab Dispos., 2008, 36(8),1637-1649.
27. Ghersi-Egea, J. F.; Strazielle, N. Brain drug delivery, drug metabolism,and multidrug resistance at the choroid plexus. Microsc. Res.Tech., 2001, 52(1), 83-88. (Pubitemid 32065031)
28. Ghersi-Egea, J. F.; Strazielle, N. Choroid plexus transporters fordrugs and other xenobiotics. J. Drug Target, 2002, 10(4), 353-357. (Pubitemid 34746317)
29. Miksys, S.; Tyndale, R. F. The unique regulation of brain cytochromeP450 2 (CYP2) family enzymes by drugs and genetics.Drug Metab Rev., 2004, 36(2), 313-333. (Pubitemid 38802491)
30. Tyndale, R. F.; Li, Y.; Li, N. Y.; Messina, E.; Miksys, S.; Sellers,E. M. Characterization of cytochrome P-450 2D1 activity in ratbrain: high-affinity kinetics for dextromethorphan. Drug MetabDispos., 1999, 27(8), 924-930. (Pubitemid 29347593)
31. Woodland, C.; Huang, T. T.; Gryz, E.; Bendayan, R.; Fawcett, J. P.Expression, activity and regulation of CYP3A in human and rodentbrain. Drug Metab Rev., 2008, 40(1), 149-168. (Pubitemid 351220645)
32. Dauchy, S.; Dutheil, F.; Weaver, R. J.; Chassoux, F.; Daumas-Duport, C.; Couraud, P. O.; Scherrmann, J. M.; De, W., I; Decleves,X. ABC transporters, cytochromes P450 and their maintranscription factors: expression at the human blood-brain barrier.J. Neurochem., 2008, 107(6), 1518-1528.
33. Dauchy, S.; Miller, F.; Couraud, P. O.; Weaver, R. J.; Weksler, B.;Romero, I. A.; Scherrmann, J. M.; De, W., I; Decleves, X. Expressionand transcriptional regulation of ABC transporters and cytochromesP450 in hCMEC/D3 human cerebral microvascular endothelialcells. Biochem. Pharmacol., 2009, 77(5), 897-909.
34. Dresser, G. K.; Spence, J. D.; Bailey, D. G. Pharmacokineticpharmacodynamicconsequences and clinical relevance of cytochromeP450 3A4 inhibition. Clin. Pharmacokinet., 2000, 38(1),41-57. (Pubitemid 30055093)
35. Riffel, A. K.; Schuenemann, E.; Vyhlidal, C. A. Regulation of theCYP3A4 and CYP3A7 promoters by members of the nuclear factorI transcription factor family. Mol. Pharmacol., 2009, 76(5), 1104-1114.
36. Kolars, J. C.; Lown, K. S.; Schmiedlin-Ren, P.; Ghosh, M.; Fang,C.; Wrighton, S. A.; Merion, R. M.; Watkins, P. B. CYP3A geneexpression in human gut epithelium. Pharmacogenetics, 1994,4(5), 247-259. (Pubitemid 24337433)
37. Anderson, G. D. Pharmacokinetic, pharmacodynamic, and pharmacogenetictargeted therapy of antiepileptic drugs. Ther. DrugMonit., 2008, 30(2), 173-180. (Pubitemid 351521644)
38. Caraco, Y.; Muszkat, M.; Wood, A. J. Phenytoin metabolic ratio: aputative marker of CYP2C9 activity in vivo. Pharmacogenetics,2001, 11(7), 587-596. (Pubitemid 32953584)
39. Pearce, R. E.; Vakkalagadda, G. R.; Leeder, J. S. Pathways ofcarbamazepine bioactivation in vitro I. Characterization of humancytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab Dispos., 2002, 30(11),1170-1179. (Pubitemid 35265822)
40. Pearce, R. E.; Uetrecht, J. P.; Leeder, J. S. Pathways of carbamazepinebioactivation in vitro: II. The role of human cytochrome P450 enzymes in the formation of 2-hydroxyiminostilbene. DrugMetab. Dispos., 2005, 33(12), 1819-1826. (Pubitemid 41697267)
41. Bauer, B.; Hartz, A. M.; Lucking, J. R.; Yang, X.; Pollack, G. M.;Miller, D. S. Coordinated nuclear receptor regulation of the effluxtransporter, Mrp2, and the phase-II metabolizing enzyme, GSTpi,at the blood-brain barrier. J. Cereb. Blood Flow Metab., 2008,28(6), 1222-1234. (Pubitemid 351733346)
42. Egnell, A. C.; Houston, B.; Boyer, S. In vivo CYP3A4 heteroactivationis a possible mechanism for the drug interaction betweenfelbamate and carbamazepine. J. Pharmacol. Exp. Ther., 2003,305(3), 1251-1262. (Pubitemid 36618005)
43. Egnell, A. C.; Houston, J. B.; Boyer, C. S. Predictive models ofCYP3A4 Heteroactivation: in vitro-in vivo scaling and pharmacophoremodeling. J. Pharmacol. Exp. Ther., 2005, 312(3), 926-937. (Pubitemid 40293750)
44. Mosher, C. M.; Tai, G.; Rettie, A. E. CYP2C9 amino acid residuesinfluencing phenytoin turnover and metabolite regio- and stereochemistry.J. Pharmacol. Exp. Ther., 2009, 329(3), 938-944.
45. Lakehal, F.; Wendum, D.; Barbu, V.; Becquemont, L.; Poupon, R.;Balladur, P.; Hannoun, L.; Ballet, F.; Beaune, P. H.; Housset, C.Phase I and phase II drug-metabolizing enzymes are expressed andheterogeneously distributed in the biliary epithelium. Hepatology,1999, 30(6), 1498-1506.
46. Nallani, S. C.; Glauser, T. A.; Hariparsad, N.; Setchell, K.; Buckley,D. J.; Buckley, A. R.; Desai, P. B. Dose-dependent inductionof cytochrome P450 (CYP) 3A4 and activation of pregnane X receptorby topiramate. Epilepsia, 2003, 44(12), 1521-1528. (Pubitemid 38020186)
47. Anderson, G. D. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology, 2004,63(10 Suppl 4), S3-S8. (Pubitemid 39532357)
48. Bolt, H. M. Rifampicin, a keystone inducer of drug metabolism:from Herbert Remmer's pioneering ideas to modern concepts. DrugMetab Rev., 2004, 36(3-4), 497-509. (Pubitemid 39456439)
49. Wang, H.; Faucette, S. R.; Gilbert, D.; Jolley, S. L.; Sueyoshi, T.;Negishi, M.; LeCluyse, E. L. Glucocorticoid receptor enhancementof pregnane X receptor-mediated CYP2B6 regulation in primaryhuman hepatocytes. Drug Metab Dispos., 2003, 31(5), 620-630. (Pubitemid 36444171)
50. Levy, R. H.; Rettenmeier, A. W.; Anderson, G. D.; Wilensky, A. J.;Friel, P. N.; Baillie, T. A.; Acheampong, A.; Tor, J.; Guyot, M.;Loiseau, P. Effects of polytherapy with phenytoin, carbamazepine,and stiripentol on formation of 4-ene-valproate, a hepatotoxic metaboliteof valproic acid. Clin. Pharmacol. Ther., 1990, 48(3), 225-235. (Pubitemid 20323648)
51. Mohanraj, R.; Brodie, M. J. Diagnosing refractory epilepsy: responseto sequential treatment schedules. Eur. J. Neurol., 2006,13(3), 277-282.
52. Neels, H. M.; Sierens, A. C.; Naelaerts, K.; Scharpe, S. L.; Hatfield,G. M.; Lambert, W. E. Therapeutic drug monitoring of oldand newer anti-epileptic drugs. Clin. Chem. Lab Med., 2004,42(11), 1228-1255. (Pubitemid 39600327)
53. Patsalos, P. N.; Perucca, E. Clinically important drug interactionsin epilepsy: interactions between antiepileptic drugs and otherdrugs. Lancet Neurol., 2003, 2(8), 473-481. (Pubitemid 36876104)
54. Patsalos, P. N.; Perucca, E. Clinically important drug interactionsin epilepsy: general features and interactions between antiepilepticdrugs. Lancet Neurol., 2003, 2(6), 347-356. (Pubitemid 38352562)
55. Patsalos, P. N.; Berry, D. J.; Bourgeois, B. F.; Cloyd, J. C.; Glauser,T. A.; Johannessen, S. I.; Leppik, I. E.; Tomson, T.; Perucca,E. Antiepileptic drugs - best practice guidelines for therapeuticdrug monitoring: a position paper by the subcommission on therapeuticdrug monitoring, ILAE Commission on Therapeutic Strategies.Epilepsia, 2008, 49(7), 1239-1276. (Pubitemid 351991390)
56. Perucca, E. Clinically relevant drug interactions with antiepilepticdrugs. Br. J. Clin. Pharmacol., 2006, 61(3), 246-255. (Pubitemid 43382623)
57. Anderson, G. D. A mechanistic approach to antiepileptic druginteractions. Ann. Pharmacother., 1998, 32(5), 554-563.
58. Anderson, G. D. Children versus adults: pharmacokinetic andadverse-effect differences. Epilepsia, 2002, 43 Suppl 3 53-59. (Pubitemid 34633697)
59. Yap, K. Y.; Chui, W. K.; Chan, A. Drug interactions betweenchemotherapeutic regimens and antiepileptics. Clin. Ther., 2008,30(8), 1385-1407.
60. Volk, H. A.; Loscher, W. Multidrug resistance in epilepsy: ratswith drug-resistant seizures exhibit enhanced brain expression of Pglycoproteincompared with rats with drug-responsive seizures.Brain, 2005, 128(Pt 6), 1358-1368. (Pubitemid 40826189)
61. Bauer, B.; Hartz, A. M.; Fricker, G.; Miller, D. S. Pregnane Xreceptor up-regulation of P-glycoprotein expression and transportfunction at the blood-brain barrier. Mol. Pharmacol., 2004, 66(3),413-419. (Pubitemid 39329239)
62. Miller, D. S. Regulation of P-glycoprotein and other ABC drugtransporters at the blood-brain barrier. Trends Pharmacol. Sci.,2010, 31(6), 246-254.
63. Bauer, B.; Hartz, A. M.; Pekcec, A.; Toellner, K.; Miller, D. S.;Potschka, H. Seizure-induced up-regulation of P-glycoprotein atthe blood-brain barrier through glutamate and cyclooxygenase-2signaling. Mol. Pharmacol., 2008, 73(5), 1444-1453. (Pubitemid 351574834)
64. Marroni, M.; Agrawal, M. L.; Kight, K.; Hallene, K. L.; Hossain,M.; Cucullo, L.; Signorelli, K.; Namura, S.; Bingaman, W.; Janigro,D. Relationship between expression of multiple drug resistanceproteins and p53 tumor suppressor gene proteins in humanbrain astrocytes. Neuroscience, 2003, 121(3), 605-617. (Pubitemid 38367500)
65. Cutler, R. G.; Mattson, M. P. The adversities of aging. Ageing Res.Rev., 2006, 5(3), 221-238.
66. Jick, H.; Zornberg, G. L.; Jick, S. S.; Seshadri, S.; Drachman, D. A.Statins and the risk of dementia. Lancet, 2000, 356(9242), 1627-1631.
67. Wolozin, B.; Kellman, W.; Ruosseau, P.; Celesia, G. G.; Siegel, G.Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3- methyglutaryl coenzyme A reductase inhibitors. Arch.Neurol., 2000, 57(10), 1439-1443.
68. Gilham, D. E.; Cairns, W.; Paine, M. J.; Modi, S.; Poulsom, R.;Roberts, G. C.; Wolf, C. R. Metabolism of MPTP by cytochromeP4502D6 and the demonstration of 2D6 mRNA in human foetaland adult brain by in situ hybridization. Xenobiotica, 1997, 27(1),111-125. (Pubitemid 27068376)
69. Matoh, N.; Tanaka, S.; Takehashi, M.; Banasik, M.; Stedeford, T.;Masliah, E.; Suzuki, S.; Nishimura, Y.; Ueda, K. Overexpressionof CYP2D6 attenuates the toxicity of MPP+ in actively dividingand differentiated PC12 cells. Gene Expr., 2003, 11(3-4), 117-124. (Pubitemid 37516645)
70. Kropp, S.; Lichtinghagen, R.; Winterstein, K.; Schlimme, J.;Schneider, U. Cytochrome P-450 2D6 and 2C19 polymorphismsand length of hospitalization in psychiatry. Clin. Lab., 2006, 52(5-6), 237-240. (Pubitemid 44430257)
71. Vogelgesang, S.; Cascorbi, I.; Schroeder, E.; Pahnke, J.; Kroemer,H. K.; Siegmund, W.; Kunert-Keil, C.; Walker, L. C.; Warzok, R.W. Deposition of Alzheimer's beta-amyloid is inversely correlatedwith P-glycoprotein expression in the brains of elderly nondementedhumans. Pharmacogenetics, 2002, 12(7), 535-541. (Pubitemid 35177083)
72. Vogelgesang, S.; Glatzel, M.; Walker, L. C.; Kroemer, H. K.; Aguzzi,A.; Warzok, R. W. Cerebrovascular P-glycoprotein expressionis decreased in Creutzfeldt-Jakob disease. Acta Neuropathol.,2006, 111(5), 436-443.
73. Vautier, S.; Fernandez, C. ABCB1: the role in Parkinson's diseaseand pharmacokinetics of antiparkinsonian drugs. Expert Opin.Drug Metab Toxicol., 2009, 5(11), 1349-1358.
74. Langford, D.; Grigorian, A.; Hurford, R.; Adame, A.; Ellis, R. J.;Hansen, L.; Masliah, E. Altered P-glycoprotein expression inAIDS patients with HIV encephalitis. J. Neuropathol. Exp. Neurol.,2004, 63(10), 1038-1047. (Pubitemid 39372588)
75. Perloff, M. D.; von Moltke, L. L.; Fahey, J. M.; Greenblatt, D. J.Induction of P-glycoprotein expression and activity by ritonavir inbovine brain microvessel endothelial cells. J. Pharm. Pharmacol.,2007, 59(7), 947-953. (Pubitemid 47051075)
76. Ronaldson, P. T.; Persidsky, Y.; Bendayan, R. Regulation of ABCmembrane transporters in glial cells: relevance to the pharmacotherapyof brain HIV-1 infection. Glia, 2008, 56(16), 1711-1735.
77. Zlokovic, B. V. The blood-brain barrier in health and chronicneurodegenerative disorders. Neuron, 2008, 57(2), 178-201.
78. Hartz, A. M.; Miller, D. S.; Bauer, B. Restoring blood-brain barrierP-glycoprotein reduces brain amyloid-beta in a mouse model ofAlzheimer's disease. Mol. Pharmacol., 2010, 77(5), 715-723.
79. Janigro, D.; Leaman, S. M.; Stanness, K. A. Dynamic modeling ofthe blood-brain barrier: a novel tool for studies of drug delivery tothe brain. Pharm. Sci. Technol. Today, 1999, 2(1), 7-12. (Pubitemid 29132899)
80. McAllister, M. S.; Krizanac-Bengez, L.; Macchia, F.; Naftalin, R.J.; Pedley, K. C.; Mayberg, M. R.; Marroni, M.; Leaman, S.; Stanness,K. A.; Janigro, D. Mechanisms of glucose transport at theblood-brain barrier: an in vitro study. Brain Res., 2001, 904(1), 20-30. (Pubitemid 32545351)
81. Stanness, K. A.; Guatteo, E.; Janigro, D. A dynamic model of theblood-brain barrier "in vitro". Neurotoxicology, 1996, 17(2), 481-496. (Pubitemid 26321348)
82. Stanness, K. A.; Westrum, L. E.; Fornaciari, E.; Mascagni, P.;Nelson, J. A.; Stenglein, S. G.; Myers, T.; Janigro, D. Morphologicaland functional characterization of an in vitro blood-brain barriermodel. Brain Res., 1997, 771(2), 329-342. (Pubitemid 27492111)
83. Stanness, K. A.; Neumaier, J. F.; Sexton, T. J.; Grant, G. A.; Emmi,A.; Maris, D. O.; Janigro, D. A new model of the blood - brain barrier:co-culture of neuronal, endothelial and glial cells under dynamicconditions. Neuroreport, 1999, 10(18), 3725-3731. (Pubitemid 30004823)
84. Cucullo, L.; Hossain, M.; Rapp, E.; Manders, T.; Marchi, N.; Janigro,D. Development of a humanized in vitro blood-brain barriermodel to screen for brain penetration of antiepileptic drugs. Epilepsia,2007, 48(3), 505-516. (Pubitemid 46365189)
85. Arisaka, T.; Mitsumata, M.; Kawasumi, M.; Tohjima, T.; Hirose,S.; Yoshida, Y. Effects of shear stress on glycosaminoglycan synthesisin vascular endothelial cells. Ann. N. Y Acad. Sci., 1995, 748543-554.
86. Desai, S. Y.; Marroni, M.; Cucullo, L.; Krizanac-Bengez, L.; Mayberg,M. R.; Hossain, M. T.; Grant, G. G.; Janigro, D. Mechanismsof endothelial survival under shear stress. Endothelium, 2002, 9(2),89-102. (Pubitemid 35252017)
87. Delaporte, E.; Renton, K. W. Cytochrome P4501A1 and cytochromeP4501A2 are downregulated at both transcriptional andpost-transcriptional levels by conditions resulting in interferonalpha/beta induction. Life Sci., 1997, 60(10), 787-796. (Pubitemid 27087271)
88. Meyer, R. P.; Podvinec, M.; Meyer, U. A. Cytochrome P450CYP1A1 accumulates in the cytosol of kidney and brain and is activatedby heme. Mol. Pharmacol., 2002, 62(5), 1061-1067. (Pubitemid 35222496)
89. Iba, M. M.; Storch, A.; Ghosal, A.; Bennett, S.; Reuhl, K. R.;Lowndes, H. E. Constitutive and inducible levels of CYP1A1 andCYP1A2 in rat cerebral cortex and cerebellum. Arch. Toxicol.,2003, 77(10), 547-554. (Pubitemid 37383746)
90. Schilter, B.; Omiecinski, C. J. Regional distribution and expressionmodulation of cytochrome P-450 and epoxide hydrolase mRNAs inthe rat brain. Mol. Pharmacol., 1993, 44(5), 990-996. (Pubitemid 23344965)
91. Granberg, L.; Ostergren, A.; Brandt, I.; Brittebo, E. B. CYP1A1and CYP1B1 in blood-brain interfaces: CYP1A1-dependent bioactivationof 7,12-dimethylbenz(a)anthracene in endothelial cells.Drug Metab Dispos., 2003, 31(3), 259-265. (Pubitemid 36249679)
92. Thuerl, C.; Otten, U.; Knoth, R.; Meyer, R. P.; Volk, B. Possiblerole of cytochrome P450 in inactivation of testosterone in immortalizedhippocampal neurons. Brain Res., 1997, 762(1-2), 47-55. (Pubitemid 27315933)
93. Knupfer, H.; Knupfer, M. M.; Hotfilder, M.; Preiss, R. P450-expression in brain tumors. Oncol. Res., 1999, 11(11-12), 523-528.
94. Harder, D. R.; Zhang, C.; Gebremedhin, D. Astrocytes function inmatching blood flow to metabolic activity. News Physiol Sci. ,2002, 17 27-31.
95. Meyer, R. P.; Knoth, R.; Schiltz, E.; Volk, B. Possible function ofastrocyte cytochrome P450 in control of xenobiotic phenytoin inthe brain: in vitro studies on murine astrocyte primary cultures.Exp. Neurol., 2001, 167(2), 376-384. (Pubitemid 32150895)
96. Hedlund, E.; Wyss, A.; Kainu, T.; Backlund, M.; Kohler, C.; Pelto-Huikko, M.; Gustafsson, J. A.; Warner, M. Cytochrome P4502D4in the brain: specific neuronal regulation by clozapine and toluene.Mol. Pharmacol., 1996, 50(2), 342-350. (Pubitemid 26265139)
97. Chinta, S. J.; Pai, H. V.; Upadhya, S. C.; Boyd, M. R.; Ravindranath,V. Constitutive expression and localization of the majordrug metabolizing enzyme, cytochrome P4502D in human brain.Brain Res. Mol. Brain Res., 2002, 103(1-2), 49-61. (Pubitemid 34775033)
98. McFayden, M. C.; Melvin, W. T.; Murray, G. I. Regional distributionof individual forms of cytochrome P450 mRNA in normaladult human brain. Biochem. Pharmacol., 1998, 55(6), 825-830. (Pubitemid 28319646)
99. Siegle, I.; Fritz, P.; Eckhardt, K.; Zanger, U. M.; Eichelbaum, M.Cellular localization and regional distribution of CYP2D6 mRNAand protein expression in human brain. Pharmacogenetics, 2001,11(3), 237-245. (Pubitemid 32319873)
100. Choudhary, D.; Jansson, I.; Stoilov, I.; Sarfarazi, M.; Schenkman,J. B. Expression patterns of mouse and human CYP orthologs(families 1-4) during development and in different adult tissues.Arch. Biochem. Biophys., 2005, 436(1), 50-61. (Pubitemid 40332424)
101. Miksys, S.; Lerman, C.; Shields, P. G.; Mash, D. C.; Tyndale, R. F.Smoking, alcoholism and genetic polymorphisms alter CYP2B6levels in human brain. Neuropharmacology, 2003, 45(1), 122-132. (Pubitemid 36700458)
102. Upadhya, S. C.; Tirumalai, P. S.; Boyd, M. R.; Mori, T.; Ravindranath,V. Cytochrome P4502E (CYP2E) in brain: constitutiveexpression, induction by ethanol and localization by fluorescencein situ hybridization. Arch. Biochem. Biophys., 2000, 373(1), 23-34. (Pubitemid 30046486)
103. Nef, P.; Heldman, J.; Lazard, D.; Margalit, T.; Jaye, M.; Hanukoglu,I.; Lancet, D. Olfactory-specific cytochrome P-450. cDNAcloning of a novel neuroepithelial enzyme possibly involved inchemoreception. J. Biol. Chem., 1989, 264(12), 6780-6785. (Pubitemid 19114785)
104. Qu, W.; Bradbury, J. A.; Tsao, C. C.; Maronpot, R.; Harry, G. J.;Parker, C. E.; Davis, L. S.; Breyer, M. D.; Waalkes, M. P.; Falck, J.R.; Chen, J.; Rosenberg, R. L.; Zeldin, D. C. Cytochrome P450CYP2J9, a new mouse arachidonic acid omega-1 hydroxylase predominantlyexpressed in brain. J. Biol. Chem., 2001, 276(27),25467-25479.
105. Voirol, P.; Jonzier-Perey, M.; Porchet, F.; Reymond, M. J.; Janzer,R. C.; Bouras, C.; Strobel, H. W.; Kosel, M.; Eap, C. B.; Baumann,P. Cytochrome P-450 activities in human and rat brain microsomes.Brain Res., 2000, 855(2), 235-243. (Pubitemid 30085495)
106. Wang, H.; Kawashima, H.; Strobel, H. W. cDNA cloning of anovel CYP3A from rat brain. Biochem. Biophys. Res. Commun.,1996, 221(1), 157-162. (Pubitemid 26136440)
107. Hagemeyer, C. E.; Rosenbrock, H.; Ditter, M.; Knoth, R.; Volk, B.Predominantly neuronal expression of cytochrome P450 isoformsCYP3A11 and CYP3A13 in mouse brain. Neuroscience, 2003,117(3), 521-529. (Pubitemid 36263148)
108. Stromstedt, M.; Warner, M.; Gustafsson, J. A. Cytochrome P450sof the 4A subfamily in the brain. J. Neurochem., 1994, 63(2), 671-676.
109. Stanley, L. A.; Copp, A. J.; Pope, J.; Rolls, S.; Smelt, V.; Perry, V.H.; Sim, E. Immunochemical detection of arylamine Nacetyltransferaseduring mouse embryonic development and inadult mouse brain. Teratology, 1998, 58(5), 174-182. (Pubitemid 28542486)
110. Belanger, G.; Barbier, O.; Hum, D. W.; Belanger, A. Molecularcloning, expression and characterization of a monkey steroid UDPglucuronosyltransferase, UGT2B19, that conjugates testosterone.Eur. J. Biochem., 1999, 260(3), 701-708. (Pubitemid 29148635)
111. de Leon, J. Glucuronidation enzymes, genes and psychiatry. Int. J.Neuropsychopharmacol., 2003, 6(1), 57-72. (Pubitemid 36373101)
112. Yu, X. Q.; Xue, C. C.; Wang, G.; Zhou, S. F. Multidrug resistanceassociated proteins as determining factors of pharmacokinetics andpharmacodynamics of drugs. Curr. Drug Metab., 2007, 8(8), 787-802. (Pubitemid 350238908)
113. Zhou, S. F.; Wang, L. L.; Di, Y. M.; Xue, C. C.; Duan, W.; Li, C.G.; Li, Y. Substrates and inhibitors of human multidrug resistanceassociated proteins and the implications in drug development. Curr.Med. Chem., 2008, 15(20), 1981-2039.
114. Zhou, S. F. Structure, function and regulation of P-glycoproteinand its clinical relevance in drug disposition. Xenobiotica, 2008,38(7-8), 802-832.
115. Franke, R. M.; Gardner, E. R.; Sparreboom, A. Pharmacogeneticsof drug transporters. Curr. Pharm. Des., 2010, 16(2), 220-230.
116. Urquhart, B. L.; Kim, R. B. Blood-brain barrier transporters andresponse to CNS-active drugs. Eur. J. Clin. Pharmacol., 2009,65(11), 1063-1070.
117. Hagenbuch, B.; Meier, P. J. The superfamily of organic aniontransporting polypeptides. Biochim. Biophys. Acta, 2003, 1609(1),1-18.
118. Tirona, R. G.; Kim, R. B. Pharmacogenomics of organic aniontransportingpolypeptides (OATP). Adv. Drug Deliv. Rev., 2002,54(10), 1343-1352.
119. Awasthi, S.; Hallene, K. L.; Fazio, V.; Singhal, S. S.; Cucullo, L.;Awasthi, Y. C.; Dini, G.; Janigro, D. RLIP76, a non-ABC transporter,and drug resistance in epilepsy. BMC Neurosci., 2005, 6 61.
120. Janigro, D.; Awasthi, S.; Awasthi, Y. C.; Sharma, R.; Yadav, S.;Singhal, S. S.; Hallene, K. RLIP76 in AED drug resistance. Epilepsia,2007, 48(6), 1218-1219.