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


CONCLUSIONS
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.
Kim
Won-Joo
WJ
Departments of Pharmacology, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul, Korea.
Lee
Ji Hyun
JH
Yi
Jihyun
J
Cho
Yang-Je
YJ
Heo
Kyoung
K
Lee
Sung Hee
SH
Kim
So Won
SW
Kim
Myeong-Kyu
MK
Kim
Kyung Hwan
KH
In Lee
Byung
B
Lee
Min Goo
MG
D000483:Alleles; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics; D002220:Carbamazepine / Q000009:adverse effects* / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics / Q000378:metabolism; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D000927:Anticonvulsants; D002220:Carbamazepine; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins; C000715087:ABCC2 protein, human