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A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy.

 Soon Ok Cho  ;  Joo Weon Lim  ;  Kyung Hwan Kim  ;  Hyeyoung Kim 
 PHARMACOGENETICS AND GENOMICS, Vol.20(4) : 249-256, 2010 
Journal Title
Issue Date
Alleles ; Anticonvulsants/adverse effects* ; Anticonvulsants/pharmacokinetics ; Carbamazepine/adverse effects* ; Carbamazepine/pharmacokinetics ; Case-Control Studies ; Cell Line ; Central Nervous System/drug effects ; Drug-Related Side Effects and Adverse Reactions/genetics ; Drug-Related Side Effects and Adverse Reactions/metabolism ; Epilepsy/drug therapy* ; Epilepsy/genetics* ; Epilepsy/metabolism ; Female ; Gene Frequency ; Humans ; Male ; Multidrug Resistance-Associated Proteins/genetics* ; Multidrug Resistance-Associated Proteins/metabolism ; Pharmacogenetics ; Polymorphism, Single Nucleotide* ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
OBJECTIVES: Multidrug resistance protein 2 (MRP2, ABCC2) is involved in the transport of antiepileptic drugs and is upregulated in the brain tissues of patients with epilepsy. Therefore, genetic variations in the MRP2 gene may affect individual drug responses to the antiepileptic agent carbamazepine.

METHODS: Associations between MRP2 polymorphisms and the adverse drug reactions (ADRs) of carbamazepine were analyzed using an integrated population genetics and molecular functional approach. In the initial case-control study, five tag single nucleotide polymorphisms in the MRP2 gene were analyzed in 146 patients with epilepsy. Patients were divided into two groups: those who experienced ADRs of the central nervous system and those who did not. An independent replication study was performed using DNA samples from 279 patients.

RESULTS: A nonsynonymous polymorphism, c.1249G>A (p.V417I, rs2273697), showed a strong association with the neurological ADR caused by carbamazepine (P=0.005). Logistic regression analysis with multiple clinical variables indicated that the presence of A allele at the MRP2 c.1249G>A locus was an independent determinant of central nervous system ADR caused by carbamazepine. Moreover, the positive association of c.1249A was reproduced in the replication study (P=0.042, joint P value of the replication=0.001). The functional study using ATPase assay and FACScan flow cytometer indicated that carbamazepine was a substrate of MRP2 and that the 417I variation selectively reduced carbamazepine transport across the cell membrane.

CONCLUSION: These results strongly suggest that the A-allele of the MRP2 single nucleotide polymorphism c.1247G>A is associated with adverse neurological drug reactions to carbamazepine.
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1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Hwan(김경환)
Kim, So Won(김소원)
Kim, Won Joo(김원주) ORCID logo https://orcid.org/0000-0002-5850-010X
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Byung In(이병인)
Lee, Sung Hee(이성희)
Lee, Ji Hyun(이지현)
Cho, Yang Je(조양제)
Heo, Kyoung(허경)
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