MRP1 polymorphisms associated with citalopram response in patients with major depression.
Multidrug resistance protein 1 (MRP1, ABCC1) transports antidepressive agents in the endothelial cells of the blood-brain barrier. Therefore, polymorphisms in the MRP1 gene may affect the treatment response of antidepressants. This study was aimed to identify the association between genetic variations in MRP1/ABCC1 and the therapeutic response to the antidepressant citalopram. One hundred and twenty-three patients who had been treated with citalopram monotherapy to control their major depressive disorder were recruited, and genotype data from 64 patients who had completed their 8-week follow-up were evaluated together with those from 100 controls. Nine MRP1 single nucleotide polymorphisms (SNPs) showing more than 5% allele frequency in the Korean population were analyzed. The c.4002G>A, a synonymous SNP in exon 28, showed a strong association with the remission state at 8 weeks (P = 0.005, odds ratio [OR], 4.7, 95% confidence interval [CI], 1.5 approximately 14.7). The c.4002G>A forms a linkage disequilibrium block with 3 other SNPs including c.5462T>A in the 3' untranslated region. Accordingly, the haplotype showed a significant association with the remission state (P = 0.014). Subsequent molecular studies also supported the association between these MRP1 polymorphisms and the citalopram response. Thus, kinetic studies using MRP1-enriched membrane vesicles revealed that citalopram is a substrate of MRP1 (Km = 1.99 microM, Vmax = 137 pmol/min per milligram protein). In addition, individuals with c.4002G>A or c.5462T>A polymorphisms showed higher MRP1 mRNA levels in peripheral blood cells. These results suggest that MRP1 polymorphisms may be a predictive marker of citalopram treatment in major depression.
Lee
Sung Hee
SH
Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
Lee
Min-Soo
MS
Lee
Ji Hyun
JH
Kim
So Won
SW
Kang
Rhee-Hun
RH
Choi
Myoung-Jin
MJ
Park
Sang Jin
SJ
Kim
Se Joo
SJ
Lee
Jae Myun
JM
Cole
Susan P C
SP
Lee
Min Goo
MG
D000328:Adult; D000368:Aged; D015283:Citalopram / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000235:genetics* / Q000523:psychology; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
D015283:Citalopram; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1