ABC Transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) Expression in the Developing Human CNS

Abstract

P-glycoprotein (P-gp/ABCB1), multidrug resistance associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) are plasma membrane efflux pumps that limit the intracellular uptake and retention of numerous lipophilic, amphipathic xeno- and endobiotics. Little is known about the neonatal and developmental expression of P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 in the human central nervous system (CNS), therefore post-mortem CNS tissue from infants born at 22^0/7–42^0/7 weeks of gestation and adults was immunostained to determine their ontogeny and cellular localization. P-gp/ABCB1 immunostaining was observed in microvessel endothelial cells as early as 22^0/7 weeks, increasing in prevalence and intensity with maturation, and later in gestation in large pyramidal neurons. MRP1/ABCC1 immunostaining was prominent early in the choroid plexus and ventricular ependyma, and noted later in large pyramidal neurons. BCRP/ABCG2 expression was limited to microvessel endothelial cells. P-gp/ABCB1, MRP1/ABCC1 and BCRP/ABCG2 in adult brain matched term newborn CNS but with more intense immunostaining. We conclude that P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 are expressed in a developmental, cell specific, fashion in the human CNS. The complementary pattern of P-gp/ABCB1 and BCRP/ABCG2 at the blood-brain with MRP1/ABCC1 at the blood-CSF barriers may limit CNS uptake and retention of drugs and toxins in neonates.

Key words

BCRP - P-glycoprotein - MRP1 - blood-brain barrier - human neonates

References

• 1 Ahdab-Barmada M, Moossy J. The neuropathology of kernicterus in the premature neonate: diagnostic problems.  J Neuropathol Exp Neurol. 1984;  43 45-56
• 2 Ak H, Ay B, Tanriverdi T. et al . Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia.  Seizure. 2007;  16 493-503
• 3 Aronica E, Gorter JA, Jansen GH. et al . Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors.  Neuroscience. 2003;  118 417-429
• 4 Aronica E, Gorter JA, Redeker S. et al . Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain.  Epilepsia. 2005;  46 849-857
• 5 Beaulieu E, Demeule M, Ghitescu L. et al . P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain.  Biochem J. 1997;  326 539-544
• 6 Bendayan R, Ronaldson PT, Gingras D. et al . In situ localization of P-gycoprotein (ABCB1) in human and rat brain.  J Histochem Cytochem. 2006;  54 1159-1167
• 7 Conlee JW, Shapiro SM. Development of cerebellar hypoplasia in jaundiced Gunn rats: a quantitative light microscopic analysis.  Acta Neuropathol. 1997;  93 450-460
• 8 Cooray HC, Blackmore CG, Maskell L. et al . Localization of breast cancer resistance protein in microvessel endothelium of human brain.  Neuro Report. 2002;  13 2059-2063
• 9 Cordon-Cardo C, O’Brien JP, Casals D. et al . Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites.  Proc Natl Acad Sci USA. 1989;  86 695-698
• 10 Debus E, Weber K, Osborn M. Monoclonal antibodies specific for glial fibrillary acidic (GFA) protein and for each of the neurofilament triplet polypeptides.  Differentiation. 1983;  25 193-203
• 11 Decleves X, Regina A, Laplanche JL. et al . Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes.  J Neurosci Res. 2000;  60 594-601
• 12 Diestra JE, Scheffer GL, Catala I. et al . Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material.  J Pathol. 2002;  198 213-219
• 13 Engidawork E, Roberts JC, Hardmeier R. et al . Expression of the multidrug resistance associated protein (MRP1) in Down syndrome brains.  J Neurol Transm Suppl. 2001;  61 35-45
• 14 Fernetti C, Pascolo L, Podda E. et al . Preparation of an antibody recognizing both human and rodent MRP1.  Biochem Biophys Res Comm. 2001;  288 1064-1068
• 15 Flens MJ, Zaman GJ, Valk P van der. et al . Tissue distribution of the multidrug resistance protein.  Am J Pathol. 1996;  148 1237-1247
• 16 Georges E, Bradley G, Gariepy J. et al . Detection of P-glycoprotein isoforms by gene-specific monoclonal antibodies.  Proc Natl Acad Sci USA. 1990;  87 152-156
• 17 Ginn PE. Immunohistochemical detection of P-glycoprotein in formalin-fixed paraffin-embedded normal and neoplastic canine tissues.  Vet Pathol. 1996;  33 533-541
• 18 Golden PL, Partridge WM. P-glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries.  Brain Res. 1999;  819 143-146
• 19 Goralski KB, Acott PD, Frasere AD. et al . Brain cyclosporin A levels are determined by ontogenic regulation of mdr1a expression.  Drug Metab Dispos. 2006;  34 288-295
• 20 Hockberger PE, Yousif L, Nam SC. Identification of acutely isolated cells from developing rat cerebellum.  Neuroimage. 1994;  1 276-287
• 21 Jette L, Tetu B, Beliveau R. High levels of P-glycoprotein detected in isolated brain capillaries.  Biochim Biophys Acta. 1993;  1150 147-154
• 22 Johnson DR, Finch RA, Lin ZP. et al . The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice.  Cancer Res. 2001;  61 1469-1476
• 23 Lazarowski A, Lubieniecki F, Camarero HT. et al . Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy.  Pediatr Neurol. 2004;  30 102-106
• 24 Lazarowski A, Caltana L, Merelli A. et al . Neuronal mdr-1 gene expression after experimental focal hypoxia: a new obstacle for neuroprotection.  J Neurol Sci. 2007;  258 84-92
• 25 Leslie EM, Deeley RG, Cole SPC. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2 and BCRP (ABCG2) in tissue defense.  Toxicol Appl Pharmacol. 2005;  204 216-237
• 26 Matsuoka Y, Okazaki M, Kitamura Y. et al . Developmental expression of P-glycoprotein (multidrug resistance gene product) in the rat brain.  J Neurobiol. 1999;  39 383-392
• 27 Nies AT, Jedlitschky, Konig J. et al . Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain.  Neuroscience. 2004;  129 349-360
• 28 Ostrow JD, Pascolo L, Brites D. et al . Molecular basis of bilirubin-induced neurotoxicity.  Trends Mol Med. 2004;  10 65-70
• 29 Pavelic ZP, Sever Z, Fontaine RN. et al . Detection of P-glycoprotein with JSB-1 monoclonal antibody in B-5 fixed and paraffin-embedded cell lines and tissues.  Sel Cancer Ther. 1989;  7 49-58
• 30 Ramos AJ, Lazarowski A, Villar MJ. et al . Transient expression of MDR-1/P-glycoprotein in a model of partial cortical devascularization.  Cell Mol Neurobiol. 2004;  24 101-107
• 31 Rao VV, Dahlheimer JL, Bardgett ME. et al . Choroid plexus epithelial expression of MDR1 P-glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal fluid drug-permeability barrier.  Proc Natl Acad Sci USA. 1999;  96 3900-3905
• 32 Regina A, Koman A, Piciotti M. et al . Mrp1 multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells.  J Neurochem. 1998;  71 705-715
• 33 Rosati A, Maniori S, Decorti G. et al . Physiological regulation of P-glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny.  Develop Growth Differ. 2003;  45 377-387
• 34 Sawasaki Y, Yamada N, Nakajima H. Developmental features of cerebellar hypoplasia and brain bilirubin levels in a mutant (Gunn) rat with hereditary hyperbilirubinemia.  J Neurochem. 1976;  27 577-583
• 35 Scheffer GL, Kool M, Heijn M. et al . Specific detection of multidrug resistance proteins MRP1, MRP2, MRP3, MRP5, and P-glycoprotein with a panel of monoclonal antibodies.  Cancer Res. 2000;  60 5269-5277
• 36 Schumacher U, Mollgard K. The multidrug-resistance P-glycoprotein (Pgp, MDR1) is an early marker of blood-brain barrier development in the microvessels of the developing human brain.  Histochem Cell Biol. 1997;  108 179-182
• 37 Seetharaman S, Barrand MA, Maskell L. et al . Multidrug resistance-related transport proteins in isolated human brain microvessels and in cells cultured from these isolates.  J Neurochem. 1998;  70 1151-1159
• 38 Sisodiya SM, Lin WR, Harding BN. et al . Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy.  Brain. 2002;  125 22-31
• 39 Sisodiya SM, Martinian L, Scheffer GL. et al . Vascular colocalization of P-glycoprotein, multidrug-resistance associated protein 1, breast cancer resistance protein and major vault protein in human epileptogenic pathologies.  Neuropathol Appl Neurobiol. 2006;  32 51-63
• 40 Toth K, Vaughn MM, Slocum HK. et al . New immunohistochemical “sandwich” staining method for mdr1 P-glycoprotein detection with JSB-1 monoclonal antibody in formalin-fixed, paraffin-embedded human tissues.  Am J Pathol. 1994;  144 227-236
• 41 Tsai C, Daood MJ, Lane RH. et al . P-glycoprotein expression in mouse brain increases with maturation.  Biol Neonate. 2002;  81 58-64
• 42 Kalken CK van, Giaccone G, Valk P van der. et al . Multidrug resistance gene (P-glycoprotein) expression in the human fetus.  Am J Pathol. 1992;  141 1063-1072
• 43 Virgintino D, Robertson D, Errede M. et al . Expression of P-glycoprotein in human cerebral cortex microvessels.  J Histochem Cytochem. 2002;  501 1671-1676
• 44 Virgintino D, Errede M, Girolamo F. et al . Fetal blood-brain barrier P-glycoprotein contributes to brain protection during human development.  J Neuropathol Exp Neurol.. 2008;  67 50-61
• 45 Volk HA, Burkhardt K, Potschka H. et al . Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures.  Neuroscience. 204;  123 751-759
• 46 Watchko JF, Daood MJ, Hansen TWR. Brain bilirubin content is increased in P-glycoprotein deficient transgenic null mutant mice.  Pediatr Res. 1998;  44 763-766
• 47 Watchko JF, Daood MJ, Mahmood B. et al . P-glycoprotein and bilirubin disposition in the neonate.  J Perinatol. 2001;  21 S43-S47
• 48 Zhang W, Mojsilovic-Petrovic J, Andrade MF. et al . The expression and functional characterization of ABCG2 in brain endothelial cells and vessels.  FASEB J. 2003;  17 2085-2087

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