Genetic variation of MRP1 associated with the treatment response in the depressive disorder

Abstract

Multidrug resistant protein 1(MRP1/ABCC1), a member of ATP binding cassette(ABC) transporter superfamily, is known as a xenobiotics efflux pump. It is expressed highly in the blood brain barrier(BBB) and choroid plexus of blood cerebrospinal fluid barrier(BCSFB) and has been implicated in altering the treatment response to psychotropic drugs such as antidepressants. This study aimed to identify the association between genetic variations in MRP1/ABCC1 and the therapeutic response to the antidepressant citalopram in the depressive disorder. One hundred and twenty three patients who had been administered citalopram monotherapy to control their major depressive disorder were recruited and genotype data from sixty four patients who had completed their eight-week follow up were evaluated together with those from one hundred 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, O.R. 4.7, 95% C.I. 1.5~14.7). The c.4002G>A forms a linkage disequilibrium(LD) block with three 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 were conducted to support 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 μM, Vmax=137 pmol/min/mg protein). In addition, individuals with A allele of c.4002G>A or c.5462T>A polymorphisms showed higher MRP1 mRNA levels in peripheral blood cells. The cause of the difference in mRNA expressions was assumed from the RNA structural changes according to the c.5462T>A which forms a LD block with c.4002G>A. These results suggest that MRP1 polymorphisms may be a predictive marker of citalopram treatment in major depression.