조현병 환자에서 아미설프라이드에 의한 고프로락틴혈증과 DRD2 유전자 Taq1A 다형성의 연관성
The Relationship between the Amisulpride-Induced Hyperprolactinemia and Taq1A Polymorphism of the Dopamine D2 Receptor Gene in Schizophrenia Patients
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프로락틴은 뇌하수체 전엽의 산호성 세포에서 분비되는유즙분비자극 호르몬으로, 항정신병약물을 복용하는 조현병 환자에서 고프로락틴혈증을 유발하는 사례가 보고되었다.1) 프로락틴 혈중농도가 여성과 남성에서 각각 25 ng/mL 와 20 ng/mL를 넘는 경우를 고프로락틴혈증으로 규정하고,2) 일반적으로 프로락틴 혈중농도가 60~100 ng/mL를 넘는 경우에 다양한 임상증상을 보이며, 그 사례로는 여성형유방, 발기부전, 사정곤란, 성욕상실, 무월경, 유루증, 골밀도감소 등과 같은 부작용을 들 수 있다.3)4) 이러한 부작용은 조현병 환자의 약물복용 순응도를 떨어뜨리고, 결과적으로 증상의 잦은 재발과 만성화를 야기한다.5)6) 항정신병약물은 뇌하수체 전엽의 도파민 D2 수용체(D2 dopamine receptor)에 길항제로 작용하여 도파민의 기능을 억제하여 프로락틴 분비를 증가시킨다.7) 항정신병약물을 복용 중인 조현병 환자를 대상으로 양전자단층촬영(positron emission tomography)을 시행한 선행 연구에서 도파민 D2 수용체 의 점유율이 높아질수록 프로락틴의 혈중농도 역시 높아짐이 밝혀졌다.8)9) 이처럼 도파민 수용체와 연관된 유전자들 중 특히 도파민D2 수용체 유전자(D2 dopamine receptor gene, 이하 DRD2) 의 Taq1A(rs1800497) 다형성은 조현병,10) 정동장애,11) 알코올의존,12) 추체외로계질환,13) 섭식 장애14) 등과 같은 정신질환들과 관련성이 있는 후보 변이로 주목받고 있다. DRD2 유전자는 염색체 11q22-23에 위치하고, Taq1A 다형성은 DRD2 유전자 코딩 부위에서부터 9.4 kb 하류방향으로 자리하고 있으며,15) Taq1A의 유전자형(genotype)으로 A1과 A2 대립유전자가 있다. Taq1A A1 대립유전자를 하나 이상 보유하고 있는군은 하나도 보유하고 있지 않은 군에 비해 선조체(striatum) 에 분포된 DRD2 수용체의 밀도가 낮았고,16-18) 양전자단층촬영(positron emission tomography)을 이용한 연구에서는A1 대립유전자를 가진 군이 그렇지 않은 군보다 도파민 수용체의 결합성능(binding potential)이 떨어졌다.18) 또 기능적으로도 A1 대립유전자를 가진 군에서 도파민 수용체가 많이분포하는 뇌영역의 포도당대사를 측정했을 때, A2 대립유전자 군에 비해 기능이 감소되어 있었다.19-21) 결과적으로 Taq1A 다형성은 DRD2 발현과 기능에 중요한 생물학적 지표(biological marker)가 될 수 있음을 의미한다. 아미설프라이드는 고용량에서는 우선적으로 시냅스 후부의 도파민 D2와 D3(DRD2, DRD3) 수용체를 차단하여 항정신병적 효과를 보이며,22)23) 저용량에서는 시냅스 전부의 DRD2, DRD3 수용체를 차단하여 항우울적 효과를 나타낸다.24) 이러한 아미설프라이드의 선택적 작용기전은 부작용 측면에서도다른 비정형 항정신병약물과 비교하여 추체외로계 부작용, 체중증가뿐만 아니라 당뇨병 유발 가능성이 낮은 장점이 있다.25-28) 하지만 아미설프라이드에 의한 내분비계 부작용의발생률은 낮게는 2%에서25)28) 높게는 36%로29) 연구마다 결과가 상이하며, 특히 아미설프라이드와 연관된 고프로락틴혈증에 대한 연구는 다른 비정형 항정신병약물에 비해 부족하다.30-34) 또한 현재까지 항정신병약물로 인한 고프로락틴혈증과 DRD2 유전자 다형성의 연관성에 대한 약물유전학 연구가 우리가 아는 한 국내에는 전무하였다. 이 연구의 목적은 약물유전학적인 관점에서 Taq1A 다형성과 아미설프라이드에 의한 고프로락틴혈증의 연관성을 살펴보는 것이다. 따라서 조현병 환자에서 DRD2와 DRD3 수용체에 선택적으로 작용하는 아미설프라이드로 인한 프로락틴의 변화를 살펴보고, 유전자형 분석을 통해 Taq1A 다형성과의 관련성을 연구했다.
Abstract
Objectives : This study was aimed to investigate the association between amisulpride-induced hyperprolactinemia and the Taq1A polymorphism in the D2 dopamine receptor gene (DRD2) in schizophrenic patients. Methods : The plasma concentrations of prolactin were measured before and after treatment with amisulpride in one hundred and twenty-five schizophrenic patients. The effect of the Taq1A variants of the DRD2 on the risk of amisulpride-induced hyperprolactinemia was the main the outcome measure. The genotyping for Taq1A (rs1800497) polymorphism was performed using TaqMan single nucleotide polymorphism (SNP) genotyping assay. Results : There was a significant difference between the prolactin level at baseline and the 6th week after treatment with amisulpride in all the subjects. However, there were no significant correlations between ΔProlactin (the difference between prolactin level at baseline and the 6th week after treatment) and the Taq1A genotypes. Conclusions : This is the first study to investigate the-correlations between the Taq1A polymorphism and the amisulpride-induced hyperprolactinemia in Korean schizophrenic patients. The current results suggested the further large-scale researches on various SNPs in the DRD2 gene will establish clear goals and provide answers to the unanswered questions described in this study.
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