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PMID: 14633964 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

ABC of oral bioavailability: transporters as gatekeepers in the gut.

Gut ·Vol. 52 ·No. 12 ·2003-12-00 ·Pages 1788-95

Dietrich CG, Geier A, Oude Elferink RP

Abstract

MDR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) are members of the family of ATP binding cassette (ABC) transporters. These are plasma membrane transporters that are expressed in various organs. The role of MDR1 and MRP2 in the hepatobiliary system is well defined; both contribute to bile formation by transport of drugs, toxins, and waste products across the canalicular membrane. As they transport exogenous and endogenous substances, they reduce the body load of potentially harmful compounds. The role of ABCG2, which is also expressed in the canalicular membrane of hepatocytes, has not yet been fully characterised. All three proteins are also expressed in the apical membrane of enterocytes where they probably control oral availability of many substances. This important "gatekeeper" function of ABC transporters has been recognised recently and is currently under further investigation. Expression and activity of these transporters in the gut may differ between individuals, due to genetic polymorphisms or pathological conditions. This will lead to individual differences in bioavailability of different drugs, toxins, and (food derived) carcinogens. Recent information on substrates, transport mechanisms, function, and regulation of expression of MDR1, MRP2, and BCRP in different species is summarised in this review.

MeSH Terms
ATP-Binding Cassette Transporters/physiology Biological Availability Drug Interactions Intestinal Mucosa/metabolism Liver/metabolism Polymorphism, Genetic Promoter Regions, Genetic
Chemicals
ATP-Binding Cassette Transporters
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Dietrich C G
Department of Gastroenterology and Hepatology, Aachen University, Germany. [email protected]
Geier A
Oude Elferink R P J
References (108)
108 references, click to expand
  1. Up-regulation of transporters of the MRP family by drugs and toxins.
    Toxicol Lett. 2001 Mar 31;120(1-3):51-7 PMID: 11323161
  2. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin.
    J Biol Chem. 2001 May 4;276(18):14581-7 PMID: 11297522
  3. Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation.
    Clin Pharmacol Ther. 2001 May;69(5):308-16 PMID: 11371998
  4. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity.
    Science. 2001 Jun 22;292(5525):2329-33 PMID: 11408620
  5. Cytochromes P450 and metabolism of xenobiotics.
    Cell Mol Life Sci. 2001 May;58(5-6):737-47 PMID: 11437235
  6. Inhibition of P-glycoprotein transport function by grapefruit juice psoralen.
    Pharm Res. 2001 Apr;18(4):432-8 PMID: 11451028
  7. Identification of functionally variant MDR1 alleles among European Americans and African Americans.
    Clin Pharmacol Ther. 2001 Aug;70(2):189-99 PMID: 11503014
  8. A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line.
    Cancer Res. 2001 Aug 15;61(16):6034-7 PMID: 11507048
  9. Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR.
    J Biol Chem. 2001 Sep 7;276(36):33309-12 PMID: 11466304
  10. Regulation of biliary drug efflux pump expression by hormones and xenobiotics.
    Toxicology. 2001 Oct 5;167(1):37-46 PMID: 11557128
  11. Role of MRP2 and GSH in intrahepatic cycling of toxins.
    Toxicology. 2001 Oct 5;167(1):73-81 PMID: 11557131
  12. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells.
    Cancer Res. 2001 Sep 15;61(18):6635-9 PMID: 11559526
  13. Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers.
    J Pharmacol Exp Ther. 2001 Oct;299(1):164-70 PMID: 11561076
  14. Promoter characterization and genomic organization of the human breast cancer resistance protein (ATP-binding cassette transporter G2) gene.
    Biochim Biophys Acta. 2001 Sep 21;1520(3):234-41 PMID: 11566359
  15. Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2.
    Mol Pharmacol. 2001 Nov;60(5):934-43 PMID: 11641421
  16. Effect of grapefruit juice on digoxin pharmacokinetics in humans.
    Clin Pharmacol Ther. 2001 Oct;70(4):311-6 PMID: 11673746
  17. Transport and metabolism of the tea flavonoid (-)-epicatechin by the human intestinal cell line Caco-2.
    Pharm Res. 2001 Oct;18(10):1420-5 PMID: 11697467
  18. CYP3A4, CYP3A5, and MDR1 in human small and large intestinal cell lines suitable for drug transport studies.
    J Pharm Sci. 2001 Nov;90(11):1736-51 PMID: 11745731
  19. Comparative studies to determine the selective inhibitors for P-glycoprotein and cytochrome P4503A4.
    AAPS PharmSci. 1999;1(4):E18 PMID: 11741214
  20. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein.
    Naunyn Schmiedebergs Arch Pharmacol. 2001 Dec;364(6):551-7 PMID: 11770010
  21. Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study.
    Lancet. 2002 Jan 5;359(9300):30-6 PMID: 11809184
  22. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.
    J Biol Chem. 2002 Jan 25;277(4):2908-15 PMID: 11706036
  23. Multidrug resistance mediated by P-glycoproteins.
    Semin Cancer Biol. 1991 Aug;2(4):213-26 PMID: 1680493
  24. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics.
    J Pharm Sci. 1998 Nov;87(11):1322-30 PMID: 9811484
  25. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis.
    J Immunol. 1998 Nov 15;161(10):5733-44 PMID: 9820555
  26. Human UDP-glucuronosyltransferases: metabolism, expression, and disease.
    Annu Rev Pharmacol Toxicol. 2000;40:581-616 PMID: 10836148
  27. Expression and localization of multidrug resistant protein mrp2 in rat small intestine.
    J Pharmacol Exp Ther. 2000 Jun;293(3):717-23 PMID: 10869369
  28. The ATP-dependent glutathione S-conjugate export pump.
    Trends Biochem Sci. 1992 Nov;17(11):463-8 PMID: 1455517
  29. Preserved organic anion transport in mutant TR- rats with a hepatobiliary secretion defect.
    Am J Physiol. 1993 Sep;265(3 Pt 1):G445-52 PMID: 8214066
  30. Clinical trials of agents that reverse multidrug resistance. A literature review.
    Cancer. 1993 Dec 15;72(12):3553-63 PMID: 8252468
  31. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport.
    Biochim Biophys Acta. 1995 Jul 17;1241(2):215-68 PMID: 7640297
  32. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.
    J Clin Invest. 1996 Jun 1;97(11):2517-24 PMID: 8647944
  33. Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation.
    Br J Pharmacol. 1996 Aug;118(7):1841-7 PMID: 8842452
  34. Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia.
    J Clin Oncol. 1997 May;15(5):1796-802 PMID: 9164187
  35. Up-regulation of P-glycoprotein expression in rat liver cells by acute doxorubicin treatment.
    Eur J Biochem. 1997 May 15;246(1):186-92 PMID: 9210482
  36. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine.
    Clin Pharmacol Ther. 1997 Sep;62(3):248-60 PMID: 9333100
  37. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors.
    J Clin Invest. 1998 Jan 15;101(2):289-94 PMID: 9435299
  38. The physiological function of drug-transporting P-glycoproteins.
    Semin Cancer Biol. 1997 Jun;8(3):161-70 PMID: 9441946
  39. Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted.
    Br J Pharmacol. 1998 May;124(2):416-24 PMID: 9641561
  40. Availability of PSC833, a substrate and inhibitor of P-glycoproteins, in various concentrations of serum.
    J Natl Cancer Inst. 1998 Aug 5;90(15):1161-6 PMID: 9701366
  41. SXR, a novel steroid and xenobiotic-sensing nuclear receptor.
    Genes Dev. 1998 Oct 15;12(20):3195-205 PMID: 9784494
  42. Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione.
    Cancer Res. 1998 Nov 15;58(22):5130-6 PMID: 9823323
  43. A multidrug resistance transporter from human MCF-7 breast cancer cells.
    Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15665-70 PMID: 9861027
  44. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes.
    Cancer Res. 1999 Jan 1;59(1):8-13 PMID: 9892175
  45. Role of P-glycoprotein in drug disposition.
    Ther Drug Monit. 2000 Feb;22(1):137-40 PMID: 10688277
  46. Comparison of furosemide and vinblastine secretion from cell lines overexpressing multidrug resistance protein (P-glycoprotein) and multidrug resistance-associated proteins (MRP1 and MRP2).
    Pharmacology. 2002;64(3):126-34 PMID: 11834888
  47. Pharmacokinetic role of P-glycoprotein in oral bioavailability and intestinal secretion of grepafloxacin in vivo.
    J Pharmacol Exp Ther. 2002 Mar;300(3):1063-9 PMID: 11861816
  48. Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco-2) cells.
    Br J Pharmacol. 2002 Mar;135(5):1263-75 PMID: 11877335
  49. Interaction of digoxin with antihypertensive drugs via MDR1.
    Life Sci. 2002 Feb 15;70(13):1491-500 PMID: 11895100
  50. Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine.
    Am J Physiol Gastrointest Liver Physiol. 2002 Apr;282(4):G720-6 PMID: 11897632
  51. Epithelial transport of anthelmintic ivermectin in a novel model of isolated proximal kidney tubules.
    Pharm Res. 1999 Oct;16(10):1570-5 PMID: 10554099
  52. The human multidrug resistance protein 2 gene: functional characterization of the 5'-flanking region and expression in hepatic cells.
    Hepatology. 1999 Dec;30(6):1507-12 PMID: 10573531
  53. Interaction of docetaxel ("Taxotere") with human P-glycoprotein.
    Jpn J Cancer Res. 1999 Dec;90(12):1380-6 PMID: 10665657
  54. P-glycoprotein- and mrp2-mediated octreotide transport in renal proximal tubule.
    Br J Pharmacol. 2000 Jan;129(2):251-6 PMID: 10694230
  55. Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation.
    J Biol Chem. 2000 Mar 24;275(12):8835-43 PMID: 10722729
  56. Active transport of the angiotensin-II antagonist losartan and its main metabolite EXP 3174 across MDCK-MDR1 and caco-2 cell monolayers.
    Br J Pharmacol. 2000 Mar;129(6):1235-43 PMID: 10725273
  57. Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions.
    Mol Pharmacol. 2000 Apr;57(4):760-8 PMID: 10727523
  58. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4.
    J Pharmacol Exp Ther. 2000 Apr;293(1):230-6 PMID: 10734174
  59. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3473-8 PMID: 10716719
  60. Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro.
    Drug Metab Dispos. 2000 Aug;28(8):895-8 PMID: 10901697
  61. Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export.
    Br J Cancer. 2000 Aug;83(3):375-83 PMID: 10917554
  62. St John's wort, a herbal antidepressant, activates the steroid X receptor.
    J Endocrinol. 2000 Sep;166(3):R11-6 PMID: 10974665
  63. Expression of members of the multidrug resistance protein family in human term placenta.
    Am J Physiol Regul Integr Comp Physiol. 2000 Oct;279(4):R1495-503 PMID: 11004020
  64. Increased drug delivery to the brain by P-glycoprotein inhibition.
    Clin Pharmacol Ther. 2000 Sep;68(3):231-7 PMID: 11014404
  65. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan.
    J Natl Cancer Inst. 2000 Oct 18;92(20):1651-6 PMID: 11036110
  66. Specificity of doxorubicin versus rhodamine-123 in assessing P-glycoprotein functionality in the LLC-PK1, LLC-PK1:MDR1 and Caco-2 cell lines.
    Eur J Pharm Sci. 2000 Sep;11(3):207-14 PMID: 11042226
  67. Induction of P-glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: a new type of drug/drug interaction.
    Clin Pharmacol Ther. 2000 Oct;68(4):345-55 PMID: 11061574
  68. The MRP2/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic.
    J Biol Chem. 2000 Oct 27;275(43):33404-8 PMID: 10938093
  69. Polymorphisms in the ABCC2 (cMOAT/MRP2) gene found in 72 established cell lines derived from Japanese individuals: an association between single nucleotide polymorphisms in the 5'-untranslated region and exon 28.
    Drug Metab Dispos. 2002 Apr;30(4):363-4 PMID: 11901087
  70. Simvastatin and lovastatin, but not pravastatin, interact with MDR1.
    J Pharm Pharmacol. 2002 Mar;54(3):419-23 PMID: 11902809
  71. The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels.
    Pharmacogenomics J. 2001;1(3):204-10 PMID: 11908757
  72. Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein.
    Anesthesiology. 2002 Apr;96(4):913-20 PMID: 11964599
  73. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine.
    Br J Clin Pharmacol. 2002 May;53(5):526-34 PMID: 11994059
  74. Multidrug resistance and response to antiretroviral treatment.
    Lancet. 2002 Jun 15;359(9323):2114; author reply 2214-5 PMID: 12086787
  75. Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors.
    J Am Soc Nephrol. 2002 Jul;13(7):1847-54 PMID: 12089380
  76. Organ-specific alterations in RAR alpha:RXR alpha abundance regulate rat Mrp2 (Abcc2) expression in obstructive cholestasis.
    Gastroenterology. 2002 Aug;123(2):599-607 PMID: 12145812
  77. Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification.
    Mol Pharmacol. 2002 Sep;62(3):638-46 PMID: 12181440
  78. Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo.
    Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12339-44 PMID: 12218177
  79. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria.
    Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15649-54 PMID: 12429862
  80. Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis.
    Gastroenterology. 2003 Jan;124(1):26-33 PMID: 12512026
  81. Suppression of intestinal polyposis in Mdr1-deficient ApcMin/+ mice.
    Cancer Res. 2003 Mar 1;63(5):895-901 PMID: 12615699
  82. Regulation of UDP glucuronosyltransferase genes.
    Curr Drug Metab. 2003 Jun;4(3):249-57 PMID: 12769669
  83. Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2).
    J Biol Chem. 2003 Jun 27;278(26):23538-44 PMID: 12702717
  84. Differential modulation of the human liver conjugate transporters MRP2 and MRP3 by bile acids and organic anions.
    J Biol Chem. 2003 Jun 27;278(26):23529-37 PMID: 12704183
  85. Constitutive rat multidrug-resistance protein 2 gene transcription is down-regulated by Y-box protein 1.
    Biochem Biophys Res Commun. 2003 Sep 26;309(3):612-8 PMID: 12963034
  86. Isolation and sequence of the promoter region of the human multidrug-resistance (P-glycoprotein) gene.
    J Biol Chem. 1987 Dec 25;262(36):17432-6 PMID: 2891692
  87. Induction of hepatic mrp2 (cmrp/cmoat) gene expression in nonhuman primates treated with rifampicin or tamoxifen.
    Arch Toxicol. 1998 Dec;72(12):763-8 PMID: 9950072
  88. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.
    Pharm Res. 1999 Mar;16(3):408-14 PMID: 10213372
  89. Grapefruit juice activates P-glycoprotein-mediated drug transport.
    Pharm Res. 1999 Apr;16(4):478-85 PMID: 10227700
  90. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2.
    Cancer Res. 1999 Jun 1;59(11):2532-5 PMID: 10363967
  91. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins.
    Mol Pharmacol. 1999 Aug;56(2):383-9 PMID: 10419558
  92. Transport of the flavonoid chrysin and its conjugated metabolites by the human intestinal cell line Caco-2.
    Biochem Pharmacol. 1999 Aug 1;58(3):431-8 PMID: 10424761
  93. Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter (cMOAT/MRP2).
    FEBS Lett. 1999 Aug 6;456(2):327-31 PMID: 10456333
  94. Transcriptional control of hepatocanalicular transporter gene expression.
    Semin Liver Dis. 2000;20(3):323-37 PMID: 11076399
  95. The effect of rifampin treatment on intestinal expression of human MRP transporters.
    Am J Pathol. 2000 Nov;157(5):1575-80 PMID: 11073816
  96. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy.
    Mol Pharmacol. 2000 Dec;58(6):1357-67 PMID: 11093774
  97. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR.
    Genes Dev. 2000 Dec 1;14(23):3014-23 PMID: 11114890
  98. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine.
    Eur J Pharm Sci. 2000 Nov;12(1):3-12 PMID: 11121729
  99. St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4.
    Clin Pharmacol Ther. 2000 Dec;68(6):598-604 PMID: 11180019
  100. Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications.
    Ann N Y Acad Sci. 2000;922:188-94 PMID: 11193894
  101. The sulphonylurea glibenclamide inhibits multidrug resistance protein (MRP1) activity in human lung cancer cells.
    Br J Pharmacol. 2001 Feb;132(3):778-84 PMID: 11159731
  102. Cytochromes P450: a success story.
    Genome Biol. 2000;1(6):REVIEWS3003 PMID: 11178272
  103. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.
    Clin Pharmacol Ther. 2001 Mar;69(3):169-74 PMID: 11240981
  104. P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin.
    Naunyn Schmiedebergs Arch Pharmacol. 2001 Mar;363(3):337-43 PMID: 11284449
  105. Effect of hydroxyzine on the transport of etoposide in rat small intestine.
    Anticancer Drugs. 2001 Mar;12(3):267-73 PMID: 11290874
  106. Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-deficient rats.
    Mol Pharmacol. 2001 May;59(5):974-80 PMID: 11306678
  107. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues.
    Cancer Res. 2001 Apr 15;61(8):3458-64 PMID: 11309308
  108. Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo.
    Carcinogenesis. 2001 May;22(5):805-11 PMID: 11323401
Article Info
Journal
Gut
Abbr.
Gut
ISSN
0017-5749
DOI
10.1136/gut.52.12.1788
Email
[email protected]
Published
2003-12-00
Pages
1788-95
Language
English
Region
England
NLM ID
2985108R
PMCID
PMC1773875
Subset
IM
External Links
PubMed source DOI: 10.1136/gut.52.12.1788 PMC Full Text View journal details
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