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Genetic variation in the ATP-binding cassette transporter gene ABCG2(BCRP) in a Swedish population
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. (Osteoporos, S Ljunghall)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
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2003 (Engelska)Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 18, nr 5, s. 359-364Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The ATP-binding cassette transporter ABCG2 (also named breast cancer resistance protein, BCRP) functions as a drug efflux transporter and is expressed at high levels in the human small intestine. The aim of this study was to screen the human ABCG2 gene for genetic variation. The regions of the gene most likely to affect function, namely the coding parts, exon/intron boundaries, 5' untranslated region and 3' untranslated region and the proposed promoter region, were included in the screening. DNA was obtained from 60 Swedish individuals. The screening was performed using a polymerase chain reaction-denaturing high-performance liquid chromatography approach followed by sequence analysis. Eight sites of genetic variation were identified. The sequence variations considered to be most likely to affect transcription level or transport function were a CTCA deletion in the 5' flanking region, a single nucleotide polymorphism (SNP) in a 5' flanking CpG island, two non-synonymous SNPs, changing valine at amino acid position 12 to methionine and glutamine at position 141 to lysine, respectively. Genotyping of these sequence variations revealed linkage between the CTCA deletion and the SNP changing glutamine 141 for lysine. This information forms the basis for future association studies to investigate the genetic basis of differences of drug disposition due to sequence variation in the ABCG2 gene.

Ort, förlag, år, upplaga, sidor
2003. Vol. 18, nr 5, s. 359-364
Nyckelord [en]
ABCG2, BCRP, ATP-binding cassette transporter, SNP, Genetic variation, Swedish population
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-65504DOI: 10.1016/S0928-0987(03)00038-1PubMedID: 12694888OAI: oai:DiVA.org:uu-65504DiVA, id: diva2:93415
Tillgänglig från: 2004-11-02 Skapad: 2004-11-02 Senast uppdaterad: 2017-11-30Bibliografiskt granskad
Ingår i avhandling
1. Interindividual Variability of Drug Transport Proteins: Focus on Intestinal Pgp (ABCB1) and BCRP (ABCG2)
Öppna denna publikation i ny flik eller fönster >>Interindividual Variability of Drug Transport Proteins: Focus on Intestinal Pgp (ABCB1) and BCRP (ABCG2)
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The appearance of adverse drug reactions is a common reason for hospitalization in Western countries. Research on underlying biological mechanisms for interindividual variability in drug response aims to better identify patients with exceptional genetic traits, disease conditions or risk of drug-drug interactions and thereby help to prevent adverse drug reactions.

Active transport mechanisms are involved in the absorption and disposition of several therapeutic agents. The main objective of this thesis was to investigate factors potentially affecting transport proteins and thus contributing to variability in drug absorption and disposition. Studies of physiological, genetic, environmental, and pathological factors were included. The main focus was the two ATP-binding cassette (ABC) transporters: P-glycoprotein 170 (Pgp) and Breast Cancer Resistance Protein (BCRP).

Quantification of transport protein mRNAs along the human intestine indicated that eight of the nine investigated drug transporters were expressed in a region-dependent manner. Effects of drug-drug interactions may therefore vary depending on the site of absorption. The genetic aspect was illustrated by identification of sequence variation in the gene encoding BCRP, the most highly expressed ABC transporter along the human intestine. Drug-drug interactions are important environmental causes of interindividual variability. An evaluation of the effects of Pgp-mediated drug-drug interactions showed that patients receiving Pgp inhibitors had elevated serum concentrations of the Pgp substrate digoxin and that digoxin concentrations were positively correlated with the number of co-administered Pgp inhibitors. The final topic in this thesis was that of drug-disease interactions. BCRP and Pgp were down-regulated during active inflammation in patients with ulcerative colitis. This may contribute to altered concentrations of drug in the intestinal mucosa during periods of inflammation and possibly to changes in drug absorption.

To summarize, results of this thesis emphasize the complex background to the interindividual variability of drug transport proteins, where physiological, genetic, environmental and pathological factors all can contribute.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2005. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 21
Nyckelord
Pharmaceutics, membrane transport proteins, ATP-Binding Cassette Transporters, P-glycoprotein, Breast Cancer Resistance Protein, Interindividual variability, Galenisk farmaci
Nationell ämneskategori
Farmaceutiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-6127 (URN)91-554-6396-7 (ISBN)
Disputation
2005-12-09, Room B42, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Handledare
Tillgänglig från: 2005-11-17 Skapad: 2005-11-17 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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