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      Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

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      MDR1 Haplotypes Modify BEN Disease Risk: A Study in Bulgarian Patients with Balkan Endemic Nephropathy Compared to Healthy Controls

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          Abstract

          Background: Balkan endemic nephropathy (BEN) is a slow progressive nephropathy with frequent occurrence of uroepithelial tumors in the upper urinary tract. Genetic factors involved in xenobiotic detoxification mechanisms may cause genetic predisposition to BEN and influence the risk for this disease. Polymorphic MDR1 variants with decreased P-glycoprotein (P-gp) activity modulate the risk for renal neoplasm. We have therefore investigated the impact of MDR1 polymorphisms on BEN manifestation. Methods: The constitutional genotype frequencies of two SNPs (C3435T and G2677T) in the MDR1 gene in 112 healthy control subjects were investigated and compared with those of 96 patients with BEN. Identification of the SNPs was done with rapid cycle real-time PCR and melting curve analysis with allele-specific probes. Results: The frequency of mutant alleles was comparable in both groups. Significant differences were revealed when the MDR1 haplotypes were analyzed. Individuals with a predicted haplotype 12 (2677G/3435T) were less frequent in BEN cases (frequency 7.3%) than in controls (16.1%, p = 0.006). We found that carriers of the haplotype 12 had a decreased risk for BEN (OR = 0.411; 0.21–0.78). Conclusions: The data suggest that haplotype 12 is protective against BEN. There is no clear molecular explanation of the MDR1 haplotype effects on the protein activity, which can explain the modified effect of the haplotype 12 on BEN risk.

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          Identification of functionally variant MDR1 alleles among European Americans and African Americans.

          J Schuetz, J McKinsey, Mary Lan … (2001)
          MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.
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            The physiological function of drug-transporting P-glycoproteins.

            Alfred Schinkel (1997)
            The mammalian drug-transporting or mdr1-type P-glycoproteins can extrude a range of structurally diverse, toxic xenobiotic compounds from cells. Our analysis of knockout mice lacking one or both of the mdr1-type P-glycoproteins indicates that a major function of these proteins is the protection of organisms against many of the toxic xenobiotics to which they can potentially be exposed in nature. P-glycoprotein confers protection by limiting the uptake of compounds from the gastrointestinal tract, and by stimulating excretion of compounds in the liver, kidney, and intestine. Moreover, P-glycoprotein in the blood-brain barrier and other blood-tissue barriers protects sensitive organs from exposure to toxic compounds that may have entered the bloodstream. Although we cannot exclude additional physiological functions for mdr1-type P-glycoproteins, these are not vital, since the mdr1-deficient mice are viable and fertile, and do not display obvious phenotypic abnormalities other than hypersensitivity to drugs.
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              Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P-glycoprotein.

              Yasuo Kurata, Shigehiro Ohdo, S Higuchi … (2002)
              Our objective was to quantitate the contribution of the genetic polymorphism of the human MDR1 gene to the bioavailability and interaction profiles of digoxin, a substrate of P-glycoprotein. The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups (n = 5 each) on the basis of genotyping for the MDR1 gene, in a 4-dose study after single doses of digoxin alone (0.5 mg orally and intravenously) and coadministered with clarithromycin (400 mg orally for 8 days). The dose of digoxin was reduced during the clarithromycin phase (0.25 mg orally and intravenously). The bioavailability of digoxin in G/G2677C/C3435, G/T2677C/T3435, and T/T2677T/T3435 subjects were 67.6% +/- 4.3%, 80.9% +/- 8.9%, and 87.1% +/- 8.4%, respectively, and the difference between G/G2677C/C3435 and T/T2677T/T3435 subjects was statistically significant (P <.05). The MDR1 variants were also associated with differences in disposition kinetics of digoxin, with the renal clearance being almost 32% lower in T/T2677T/T3435 subjects (1.9 +/- 0.1 mL/min per kilogram) than G/G2677C/C3435 subjects (2.8 +/- 0.3 mL/min per kilogram), and G/T2677C/T3435 subjects having an intermediate value (2.1 +/- 0.6 mL/min per kilogram). Coadministration of clarithromycin did not consistently affect digoxin clearance or renal clearance. However, a significant increase in digoxin bioavailability was observed in G/G2677C/C3435 subjects (67.6% +/- 4.3% versus 85.4% +/- 6.1%; P <.05) but not in the other 2 genotype groups. The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P-glycoprotein-mediated drug interaction
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                Author and article information

                Journal
                Journal ID (publisher-id): NEE
                Journal ID (nlm-ta): Nephron Exp Nephrol
                Journal ID (doi): 10.1159/issn.1660-2129
                Title: Cardiorenal Medicine
                Publisher: S. Karger AG
                ISSN (Electronic): 1660-2129
                Publication date Subscription-year: 2004
                Publication date (Print): January 2004
                Publication date (Electronic): 17 November 2004
                Volume: 96
                Issue: 1
                Pages: e7-e13
                Affiliations
                Departments of aMedical Genetics and bNephrology, Medical University, Sofia, Bulgaria; cDepartment of Clinical Chemistry, Georg August University, Göttingen, Germany
                Article
                Publisher ID: 75571 Other ID: Nephron Exp Nephrol 2004;96:e7–e13
                DOI: 10.1159/000075571
                PubMed ID: 14752243
                SO-VID: 29776250-947f-4776-8bff-639b30f23a0f
                Copyright © © 2004 S. Karger AG, Basel
                License:

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Date received : 22 January 2003
                Date accepted : 12 September 2003
                Page count
                Figures: 1, Tables: 3, References: 32, Pages: 1
                Categories
                Subject: Original Paper

                ScienceOpen disciplines: Cardiovascular Medicine,Nephrology
                Keywords: Balkan endemic nephropathy,Bulgarian population,SNP analysis,Haplotyping,<italic>MDR1</italic>
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine, Nephrology
                Keywords: Balkan endemic nephropathy, Bulgarian population, SNP analysis, Haplotyping, <italic>MDR1</italic>

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