Influence of genetic polymorphisms on intestinal expression and rifampicin-type induction of ABCC2 and on bioavailability of talinolol

Objectives To evaluate whether ABCC2 gene polymorphisms are associated with expression and/or function of the efflux pump. Methods We investigated the allele frequency of ABCC2 -24C>T, -23G>A, c.1249G>A, c.1446C>G, c.1457C>T, c.2302C>T, c.2366C>T, c.3542G>T, c.3561G>A, c.3563T>A, c.3972C>T, c.4348G>A, and 4544G>A in 374 nonrelated German healthy volunteers and determined the impact on duodenal mRNA and protein content of ABCC2. For functional analysis, the disposition of intravenously (30 mg) and orally administered talinolol (100 mg) was measured among 31 individuals. Moreover, the effects of rifampicin-type induction (600 mg, 8 days) of duodenal ABCC2 were quantified in 22 participants with regard to genetic polymorphisms. Results The allele frequencies were 18.3% (-24T), 21.1% (1249A), 1.4% (1446G), 0.1% (3542T), 4.5% (3563A), 34.2% (3972T), and 4.4% (4544A); carriers of -23G>A, 1457C>T, 2302C>T, 2366C>T, 3561G>A, and 4348G>A were not identified. The -24T allele was in strong linkage with 3972T, and 3563A with 4544A, whereas 1249A was weakly linked with other variant alleles. None of the single nucleotide polymorphisms investigated influenced significantly intestinal ABCC2 mRNA and protein content. The variant ABCC2 1249G>A (V417I), however, was associated with lower oral bioavailability (P=0.001), and increased residual clearance of intravenous talinolol (P=0.021). Intestinal ABCC2 mRNA and protein expression were upregulated by rifampicin treatment, a genetic influence could be detected in only four cases heterozygote for 3563T>A or 4544G>A. Conclusion The 1249G>A (V417I) polymorphism is obviously associated with higher activity of the intestinal transporter.

[1]  S. Mertens-Talcott,et al.  Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. , 2007, Journal of pharmaceutical sciences.

[2]  J. Verweij,et al.  Irinotecan‐induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein , 2007, Clinical pharmacology and therapeutics.

[3]  P. Neuvonen,et al.  Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics , 2006, Pharmacogenetics and genomics.

[4]  T. Eschenhagen,et al.  High‐dose methotrexate in pediatric acute lymphoblastic leukemia: Impact of ABCC2 polymorphisms on plasma concentrations , 2006, Clinical pharmacology and therapeutics.

[5]  K. Verbeke,et al.  Multidrug Resistance Protein 2 Genetic Polymorphisms Influence Mycophenolic Acid Exposure in Renal Allograft Recipients , 2006, Transplantation.

[6]  D. Kroetz.  Role for drug transporters beyond tumor resistance: hepatic functional imaging and genotyping of multidrug resistance transporters for the prediction of irinotecan toxicity. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Michel Eichelbaum,et al.  Interindividual variability of canalicular ATP‐binding‐cassette (ABC)–transporter expression in human liver , 2006, Hepatology.

[8]  Supratim Choudhuri,et al.  Structure, Function, Expression, Genomic Organization, and Single Nucleotide Polymorphisms of Human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) Efflux Transporters , 2006, International journal of toxicology.

[9]  M. Ratain,et al.  1249G>A polymorphism of ABCC2 (MRP2) is associated with altered gene expression in human liver. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  V. Vollrath,et al.  Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. , 2006, The Biochemical journal.

[11]  I. Cascorbi,et al.  Simvastatin does not influence the intestinal P-glycoprotein and MPR2, and the disposition of talinolol after chronic medication in healthy subjects genotyped for the ABCB1, ABCC2 and SLCO1B1 polymorphisms. , 2006, British journal of clinical pharmacology.

[12]  H. Kroemer,et al.  Intestinal expression of P‐glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate–glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans , 2006, Clinical pharmacology and therapeutics.

[13]  M. Vore,et al.  The Role of Protein Synthesis and Degradation in the Post-Transcriptional Regulation of Rat Multidrug Resistance-Associated Protein 2 (Mrp2, Abcc2) , 2005, Molecular Pharmacology.

[14]  A. Telenti,et al.  Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo , 2005, Pharmacogenetics & Genomics.

[15]  H. Kroemer,et al.  VARIABLE EXPRESSION OF MRP2 (ABCC2) IN HUMAN PLACENTA: INFLUENCE OF GESTATIONAL AGE AND CELLULAR DIFFERENTIATION , 2005, Drug Metabolism and Disposition.

[16]  W. Weimar,et al.  Cyclosporine Interacts with Mycophenolic Acid by Inhibiting the Multidrug Resistance‐Associated Protein 2 , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[17]  Michael Zschiesche,et al.  Carbamazepine regulates intestinal P‐glycoprotein and multidrug resistance protein MRP2 and influences disposition of talinolol in humans , 2004, Clinical pharmacology and therapeutics.

[18]  Y. Sugiyama,et al.  Characterization of the Cellular Localization, Expression Level, and Function of SNP Variants of MRP2/ABCC2 , 2004, Pharmaceutical Research.

[19]  H. Kroemer,et al.  CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects , 2004, Clinical pharmacology and therapeutics.

[20]  R. O. Oude Elferink,et al.  ABC of oral bioavailability: transporters as gatekeepers in the gut , 2003, Gut.

[21]  C. Gartung,et al.  Constitutive rat multidrug-resistance protein 2 gene transcription is down-regulated by Y-box protein 1. , 2003, Biochemical and biophysical research communications.

[22]  S. Kliewer.  The nuclear pregnane X receptor regulates xenobiotic detoxification. , 2003, The Journal of nutrition.

[23]  K. Audus,et al.  Efflux transporters of the human placenta. , 2003, Advanced drug delivery reviews.

[24]  Werner Siegmund,et al.  The effects of the human MDR1 genotype on the expression of duodenal P‐glycoprotein and disposition of the probe drug talinolol , 2002, Clinical pharmacology and therapeutics.

[25]  M. Kasuga,et al.  Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects. , 2002, Biological & pharmaceutical bulletin.

[26]  C. Klaassen,et al.  Expression of rat Multidrug Resistance Protein 2 (Mrp2) in male and female rats during normal and pregnenolone-16alpha-carbonitrile (PCN)-induced postnatal ontogeny. , 2002, Toxicology.

[27]  Y. Sugiyama,et al.  Reduced Gastrointestinal Toxicity Following Inhibition of the Biliary Excretion of Irinotecan and Its Metabolites by Probenecid in Rats , 2002, Pharmaceutical Research.

[28]  Y. Sugiyama,et al.  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. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[29]  H. Kroemer,et al.  Stereoselective disposition of talinolol in man. , 2002, Journal of pharmaceutical sciences.

[30]  Paul T Tarr,et al.  Regulation of Multidrug Resistance-associated Protein 2 (ABCC2) by the Nuclear Receptors Pregnane X Receptor, Farnesoid X-activated Receptor, and Constitutive Androstane Receptor* , 2002, The Journal of Biological Chemistry.

[31]  K. Ito,et al.  Mutation of Trp1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (MRP2) (ABCC2), alters substrate specificity and results in loss of methotrexate transport activity. , 2001, The Journal of biological chemistry.

[32]  Y. Sugiyama,et al.  Charged amino acids in the transmembrane domains are involved in the determination of the substrate specificity of rat Mrp2. , 2001, Molecular pharmacology.

[33]  S. Higuchi,et al.  Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. , 2001, Pharmacogenetics.

[34]  S. Ryu,et al.  Identification of Basic Residues Involved in Drug Export Function of Human Multidrug Resistance-associated Protein 2* , 2000, The Journal of Biological Chemistry.

[35]  M. Fromm,et al.  The effect of rifampin treatment on intestinal expression of human MRP transporters. , 2000, The American journal of pathology.

[36]  Michael Zschiesche,et al.  Induction of P‐glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction , 2000, Clinical pharmacology and therapeutics.

[37]  D. Keppler,et al.  Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. , 1999, Biochimica et biophysica acta.

[38]  H. Takano,et al.  The human multidrug resistance protein 2 gene: Functional characterization of the 5′‐flanking region and expression in hepatic cells , 1999, Hepatology.

[39]  R. Oertel,et al.  Intestinal secretion of intravenous talinolol is inhibited by luminal R‐verapamil , 1999, Clinical pharmacology and therapeutics.

[40]  S. Sakisaka,et al.  [Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome]. , 1999, Fukuoka igaku zasshi = Hukuoka acta medica.

[41]  C. Regårdh,et al.  Radioligand-Binding Assay Employing P-Glycoprotein-Overexpressing Cells: Testing Drug Affinities to the Secretory Intestinal Multidrug Transporter , 1998, Pharmaceutical Research.

[42]  D. Schrenk,et al.  Sequence analysis and functional characterization of the 5'-flanking region of the rat multidrug resistance protein 2 (mrp2) gene. , 1998, Biochemical and biophysical research communications.

[43]  W. Kirch,et al.  Direct demonstration of small intestinal secretion and site‐dependent absorption of the β‐blocker talinolol in humans , 1996, Clinical pharmacology and therapeutics.

[44]  D. Brockmeier,et al.  Site‐Dependent Small Intestinal Absorption of the Ace Inhibitor Ramipril , 1996 .

[45]  H. Kroemer,et al.  Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex , 2007, The Pharmacogenomics Journal.

[46]  G. Aithal,et al.  Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. , 2007, Gastroenterology.

[47]  D. Keppler,et al.  A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2). , 2003, American journal of physiology. Gastrointestinal and liver physiology.

[48]  P. Ader,et al.  P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound. , 1998, International journal of clinical pharmacology and therapeutics.