OCT2、DRD2和DRD3遗传多态性对普拉克索药代动力和药效学的影响
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摘要
很多因素可以导致药物反应个体差异,例如年龄、性别、疾病状态和遗传等。遗传药理学研究发现药物代谢酶、受体和转运体的遗传多态性是药物反应个体差异的决定因素。
普拉克索是临床用于治疗帕金森病的多巴胺受体激动剂。它为新型的非麦角碱类多巴胺受体激动剂,对多巴胺D2类受体具有高度选择性,对D2类受体的亲和力依次为D3>D2>D4。目前对早期的帕金森病患者提倡首选多巴胺受体激动剂治疗,晚期可与左旋多巴合用,这样可以尽量延缓左旋多巴开始治疗的时间和减少左旋多巴的剂量,以避免由于长期使用左旋多巴导致的疗效衰退以及引起症状波动、运动障碍和精神症状等不良反应,而且普拉克索对多巴胺神经有保护作用,可大大延缓病情的发展。普拉克索的药代动力学特点为吸收迅速,约2小时达到血药浓度高峰,生物利用度高于90%,食物对普拉克索的吸收影响很小,其在体内分布广泛,表观分布容积约为500L,与血浆蛋白的结合率约为15%,半衰期在健康的年轻人平均为8小时,在老年人大概为12小时。普拉克索的消除途径主要是通过肾脏,90%以原型从肾脏分泌排泄。研究表明普拉克索在肾脏的分泌主要由有机阳离子转运体2(organic cation transporter 2,0CT2)介导。但普拉克索在临床实际应用中存在显著的个体差异。由于它不被酶代谢,所以有机阳离子转运体2和它作用的靶受体DRD2和DRD3的遗传多态性是导致它个体差异的重要因素。
OCT2是肾脏表达最丰富的一种有机阳离子转运体,其底物包括体内多种生物活性物质和多种药物如：多巴胺、二甲双胍、金刚烷胺、西咪替丁等。近年来,OCT2基因上已陆续发现多个单核苷酸多态性(SNP),但很多SNP都存在显著的种族差异性,例如Leabman的研究发现M165工和R400C两种突变只出现在非裔美国人中,K432Q突变在非裔美国人和墨西哥裔美国人存在,而A270S突变在不同种族中都存在,并且频率高达12.7%。进一步功能研究显示,M165I和R400C两种突变显著降低了蛋白的最大转运速率。R400C和K432Q突变显示出对抑制剂TBA的敏感性增强,而突变频率最高的A270S突变对抑制剂TBA的敏感性减弱。韩国研究者IS Song的研究发现A270S突变导致转运体最大转运速率Vmax与野生型相比显著降低,在健康受试者的临床实验发现,该突变影响二甲双胍的药代动力学特征,突变后AUC和Cmax都显著升高,CL／F显著降低,并且呈现基因剂量效应。
多巴胺受体(DR)属于G蛋白偶联受体超家族。目前已知有五种DR(D1-D5),根据生化反应和药理生理特性的不同,将五种DR分为D1类和D2类受体。D1类受体包括D1和D5,兴奋时激活腺苷酸环化酶,使cAMP水平增加；D2类受体包括D2、D3和D4,兴奋时抑制腺苷酸环化酶,使cAMP水平降低。围绕DR和帕金森病的研究主要集中在D2和D3。多巴胺受体D2 (DRD2)存在以下几个突变：启动子区-141C Ins/Del突变；Taq1A RFLP;内含子2中的(CA)n二核苷酸短串联重复多态性；及三个错义突变：Ser311Cys, Pro310Ser, Val96Ala。功能研究显示,在Taq1A多态性位点携带A1等位基因的个体其纹状体DRD2受体密度降低,并且影响与底物结合的特异性；DRD3基因位于3号染色体。目前已发现的突变有Ser9Gly和位于第5内含子的MspI RFLP。Ser9Gly突变位于DRD3蛋白胞外的氨基端,对蛋白嵌入胞膜有影响,后又有研究表明9Gly突变增强受体与多巴胺的亲和力。
基于以上研究背景,本课题旨在查明OCT2808G>T突变在健康人和帕金森患者的分布特征,该突变是否与帕金森病的遗传易患性相关；通过严谨的临床实验设计查明OCT2808G>T突变在健康受试者对治疗帕金森病药物普拉克索药代动力学的影响；通过严谨的临床实验设计,研究DRD2和DRD3常见遗传突变对普拉克索在帕金森病人药效的影响。
本课题的主要研究结果如下：
1.在汉族健康志愿者,OCT2808G>T突变的T等位基因频率为11.4%；在原发性帕金森病患者,突变的T等位基因频率为3.1%,显著低于健康人群。表明OCT2808G>T突变与帕金森病的遗传易患相关,该突变对帕金森病来说可能是一遗传保护因子。
2.建立简单、灵敏的LC-MS/MS方法检测体内盐酸普拉克索血药浓度。
3.OCT2808G>T基因多态性影响普拉克索的药代特点。携带突变等位基因的受试者组普拉克索的Cmax和AUC显著高于野生型纯和子组,口服清除率则显著低于野生型纯和子组。
4.在中国的帕金森患者中,DRD3 Ser9Gly多态性和普拉克索的疗效显著相关,突变后有效率显著降低,DRD2 Taq1A多态性与普拉克索的疗效无显著相关。但需要更大范围和多剂量的临床试验进一步验证多巴胺受体遗传多态性对普拉克索疗效的影响。
总之,本项目从分子水平、健康受试者和临床病人水平对普拉克索的药物反应个体差异提供了遗传药理水平的解释,为临床合理应用普拉克索提供了实验依据和理论指导,服用普拉克索的帕金森患者先行进行OCT2、DRD2和DRD3基因型检测可能在获得更好的疗效及避免不良反应等方面有优势。
Many reason can resulted in interindividual variability in drug response, such as year, sex, disease and genetics. Pharmacogenetics studies indicate that inherited variation of drug-metabolizing enzymes, receptors or transporters is the determination of interindividual variability in drug response
Pramipexole, a novel non-ergot dopamine receptor agonist, has selective activity at the D2 subfamily of dopamine receptors (D2, D3 and D4 receptor subtypes), binding with higher affinity to D3 than to D2 or D4 receptor subtypes. It can be used alone in early Parkinson's disease and provide sufficient relief of symptoms. In addition, this drug is used as add on therapy to levodopa in patients with advanced Parkinson's disease. With long-term levodopa therapy, many patients will develop dyskinesias or motor fluctuations. Dopamine agonists mimic dopamine and act directly on dopamine receptors in the brain. They are not as effective as levodopa in controlling symptoms, but they have the benefit of postponing the need for levodopa therapy or reducing the amount of levodopa needed to control symptoms, which in turn may help delay the onset of levodopa-related side effects. Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%. Pramipexole is extensively distributed, having a volume of distribution of about 500 L range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers, pramipexole is secreted by the renal tubules mediated by the organic cation transport system. However, there is marked interindividual variability in therapeutic responses and adverse drug reactions to pramipexole. It is thought that genetic variations in the gene encoding transporter and dopamine receptor are important factors in determining interindividual variability in drug response.
OCT2 mainly expressed in kidney, its substrate include many endogenous bioactive amines and clinically used drugs such as as dopamine, norepinephrine, cimetidine, procainamide and metformin. Recently, many SNP have been found in OCT2 gene, and there is significant ethnic difference in distribution of SNP. M165I and R400C were present only in the African-American population sample, and K432Q was present in both the African-American and Mexican-American population samples. A270S was present in all of the populations screened and had a particularly high allele frequency over all populations (12.7%). Function study showed that decreased inhibition of the A270S variant by TBA. IS Song reported that the Vmax of the c.808G>T variant was significantly lower compared with the reference. Clinical study showed that 808G>T variant influence the characteristic of metformin pk, sbjects with SLC22A2 808G>T variant genotypes had significantly higher Cmax and AUC values, but lower Cl/F), Vd/F values, as compared to the SLC22A2 reference genotype group, and it had the gene dose effect.
Dopamine receptor belongs to the G protein coupled superfamily. Now five recepter (D1-D5) had been cloned. Based on their biochemical and physiological and pharmaolgical nature, they are divied into two subfamily: D1 and D2 subfamily.
D1 subfamily include D1 and D5 which activate the adenylclase resulted in the increase the cAMP; and D2 subfamily include D2、D3 and D4 which inhibite the adenylclase resulted in the decrease the cAMP. The study between the correlation of DR and Parkinson'disease focused on DRD2 and DRD3. Several polymorphisms had been found in DRD2 including-141C Ins/Del variation in promoter, Taq1A RFLP, (CA)n STR, and three nonsynonymous mutation:Ser311Cys, Pro310Ser, Val96Ala.
Studies have showed that DRD2 TaqIA polymorphism is associated with striatal dopamine D2 receptor density and affect the affinity for substrate. DRD3 gene located in chromosome 3. dopamine receptor D3 gene (DRD3) displays a number of single nucleotide polymorphisms(SNPs), and most frequently studied SNP is the Ser9Gly and MspI RFLP. A report using an in vitro expression system found that the receptors encoded by allele glycine demonstrated a significantly greater affinity for dopamine
Based on these information, our studies aimed to clarify the frequency of OCT2 808G>T in healthy subjects and Parkinson's pations and evaluate the association between OCT2 808G>T mutation and genetic risk for Parkinson's disease. We also investigated the effect of OCT2 808G>T polymorphism on PK of pramipexole and the effect of the common variation of DRD2 and DRD3 on drug response in Parkinson's pation with pramipexole treatment.
The present series studies found that:
1) The frequencies of the OCT 808G>T variant alleles in healthy subjects and Parkinson's pations were 11.4% and 3.1% respectively. The frequencies in Parkinson's pations was significantly lower than in healthy subjects. It demonstrated that there was correlation between OCT2 808G>T mutation and genetic risk for Parkinson's, and the mutation may be a protective factor for Parkinson's disease.
2) To develop a LC-MS/MS method for the determination of pramipexole in human plasma.
3) OCT2 808G>T polymorphism had effect the pharmacokinetics of pramipexole. The Cmax and AUC in subjects carring variant allele were significantly higher than in wild type subjects and the CL/F was significant lower.
4) DRD3 Ser9Gly polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with PD. The response rates for pramipexole treatment was significantly higher in Ser/Ser group (60%) compared with the group containing Gly allel (13%). When the subjects were grouped by DRD2 Taq1A polymorphism, there were no significant differences among three Taq1A genotype. A large-scale and multi-dose group study in patients with parkinson'disease is necessary for evaluating the impact of the genetic polymorphisms of dopamine receptor on therapeutic effects of pramipexole.
In conclusion, our study provide mechanism to the individual differences in drug response of pramipexole from molecular level, healthy subjects level and patientslevel and provided useful information for the clinical use of pramipexole. Before taking pramipexle patients were genotyped for OCT2、DRD2 and DRD3 and would get better therapeutic effect and little adverse reaction.
普拉克索是临床用于治疗帕金森病的多巴胺受体激动剂。它为新型的非麦角碱类多巴胺受体激动剂,对多巴胺D2类受体具有高度选择性,对D2类受体的亲和力依次为D3>D2>D4。目前对早期的帕金森病患者提倡首选多巴胺受体激动剂治疗,晚期可与左旋多巴合用,这样可以尽量延缓左旋多巴开始治疗的时间和减少左旋多巴的剂量,以避免由于长期使用左旋多巴导致的疗效衰退以及引起症状波动、运动障碍和精神症状等不良反应,而且普拉克索对多巴胺神经有保护作用,可大大延缓病情的发展。普拉克索的药代动力学特点为吸收迅速,约2小时达到血药浓度高峰,生物利用度高于90%,食物对普拉克索的吸收影响很小,其在体内分布广泛,表观分布容积约为500L,与血浆蛋白的结合率约为15%,半衰期在健康的年轻人平均为8小时,在老年人大概为12小时。普拉克索的消除途径主要是通过肾脏,90%以原型从肾脏分泌排泄。研究表明普拉克索在肾脏的分泌主要由有机阳离子转运体2(organic cation transporter 2,0CT2)介导。但普拉克索在临床实际应用中存在显著的个体差异。由于它不被酶代谢,所以有机阳离子转运体2和它作用的靶受体DRD2和DRD3的遗传多态性是导致它个体差异的重要因素。
OCT2是肾脏表达最丰富的一种有机阳离子转运体,其底物包括体内多种生物活性物质和多种药物如：多巴胺、二甲双胍、金刚烷胺、西咪替丁等。近年来,OCT2基因上已陆续发现多个单核苷酸多态性(SNP),但很多SNP都存在显著的种族差异性,例如Leabman的研究发现M165工和R400C两种突变只出现在非裔美国人中,K432Q突变在非裔美国人和墨西哥裔美国人存在,而A270S突变在不同种族中都存在,并且频率高达12.7%。进一步功能研究显示,M165I和R400C两种突变显著降低了蛋白的最大转运速率。R400C和K432Q突变显示出对抑制剂TBA的敏感性增强,而突变频率最高的A270S突变对抑制剂TBA的敏感性减弱。韩国研究者IS Song的研究发现A270S突变导致转运体最大转运速率Vmax与野生型相比显著降低,在健康受试者的临床实验发现,该突变影响二甲双胍的药代动力学特征,突变后AUC和Cmax都显著升高,CL／F显著降低,并且呈现基因剂量效应。
多巴胺受体(DR)属于G蛋白偶联受体超家族。目前已知有五种DR(D1-D5),根据生化反应和药理生理特性的不同,将五种DR分为D1类和D2类受体。D1类受体包括D1和D5,兴奋时激活腺苷酸环化酶,使cAMP水平增加；D2类受体包括D2、D3和D4,兴奋时抑制腺苷酸环化酶,使cAMP水平降低。围绕DR和帕金森病的研究主要集中在D2和D3。多巴胺受体D2 (DRD2)存在以下几个突变：启动子区-141C Ins/Del突变；Taq1A RFLP;内含子2中的(CA)n二核苷酸短串联重复多态性；及三个错义突变：Ser311Cys, Pro310Ser, Val96Ala。功能研究显示,在Taq1A多态性位点携带A1等位基因的个体其纹状体DRD2受体密度降低,并且影响与底物结合的特异性；DRD3基因位于3号染色体。目前已发现的突变有Ser9Gly和位于第5内含子的MspI RFLP。Ser9Gly突变位于DRD3蛋白胞外的氨基端,对蛋白嵌入胞膜有影响,后又有研究表明9Gly突变增强受体与多巴胺的亲和力。
基于以上研究背景,本课题旨在查明OCT2808G>T突变在健康人和帕金森患者的分布特征,该突变是否与帕金森病的遗传易患性相关；通过严谨的临床实验设计查明OCT2808G>T突变在健康受试者对治疗帕金森病药物普拉克索药代动力学的影响；通过严谨的临床实验设计,研究DRD2和DRD3常见遗传突变对普拉克索在帕金森病人药效的影响。
本课题的主要研究结果如下：
1.在汉族健康志愿者,OCT2808G>T突变的T等位基因频率为11.4%；在原发性帕金森病患者,突变的T等位基因频率为3.1%,显著低于健康人群。表明OCT2808G>T突变与帕金森病的遗传易患相关,该突变对帕金森病来说可能是一遗传保护因子。
2.建立简单、灵敏的LC-MS/MS方法检测体内盐酸普拉克索血药浓度。
3.OCT2808G>T基因多态性影响普拉克索的药代特点。携带突变等位基因的受试者组普拉克索的Cmax和AUC显著高于野生型纯和子组,口服清除率则显著低于野生型纯和子组。
4.在中国的帕金森患者中,DRD3 Ser9Gly多态性和普拉克索的疗效显著相关,突变后有效率显著降低,DRD2 Taq1A多态性与普拉克索的疗效无显著相关。但需要更大范围和多剂量的临床试验进一步验证多巴胺受体遗传多态性对普拉克索疗效的影响。
总之,本项目从分子水平、健康受试者和临床病人水平对普拉克索的药物反应个体差异提供了遗传药理水平的解释,为临床合理应用普拉克索提供了实验依据和理论指导,服用普拉克索的帕金森患者先行进行OCT2、DRD2和DRD3基因型检测可能在获得更好的疗效及避免不良反应等方面有优势。
Many reason can resulted in interindividual variability in drug response, such as year, sex, disease and genetics. Pharmacogenetics studies indicate that inherited variation of drug-metabolizing enzymes, receptors or transporters is the determination of interindividual variability in drug response
Pramipexole, a novel non-ergot dopamine receptor agonist, has selective activity at the D2 subfamily of dopamine receptors (D2, D3 and D4 receptor subtypes), binding with higher affinity to D3 than to D2 or D4 receptor subtypes. It can be used alone in early Parkinson's disease and provide sufficient relief of symptoms. In addition, this drug is used as add on therapy to levodopa in patients with advanced Parkinson's disease. With long-term levodopa therapy, many patients will develop dyskinesias or motor fluctuations. Dopamine agonists mimic dopamine and act directly on dopamine receptors in the brain. They are not as effective as levodopa in controlling symptoms, but they have the benefit of postponing the need for levodopa therapy or reducing the amount of levodopa needed to control symptoms, which in turn may help delay the onset of levodopa-related side effects. Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%. Pramipexole is extensively distributed, having a volume of distribution of about 500 L range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers, pramipexole is secreted by the renal tubules mediated by the organic cation transport system. However, there is marked interindividual variability in therapeutic responses and adverse drug reactions to pramipexole. It is thought that genetic variations in the gene encoding transporter and dopamine receptor are important factors in determining interindividual variability in drug response.
OCT2 mainly expressed in kidney, its substrate include many endogenous bioactive amines and clinically used drugs such as as dopamine, norepinephrine, cimetidine, procainamide and metformin. Recently, many SNP have been found in OCT2 gene, and there is significant ethnic difference in distribution of SNP. M165I and R400C were present only in the African-American population sample, and K432Q was present in both the African-American and Mexican-American population samples. A270S was present in all of the populations screened and had a particularly high allele frequency over all populations (12.7%). Function study showed that decreased inhibition of the A270S variant by TBA. IS Song reported that the Vmax of the c.808G>T variant was significantly lower compared with the reference. Clinical study showed that 808G>T variant influence the characteristic of metformin pk, sbjects with SLC22A2 808G>T variant genotypes had significantly higher Cmax and AUC values, but lower Cl/F), Vd/F values, as compared to the SLC22A2 reference genotype group, and it had the gene dose effect.
Dopamine receptor belongs to the G protein coupled superfamily. Now five recepter (D1-D5) had been cloned. Based on their biochemical and physiological and pharmaolgical nature, they are divied into two subfamily: D1 and D2 subfamily.
D1 subfamily include D1 and D5 which activate the adenylclase resulted in the increase the cAMP; and D2 subfamily include D2、D3 and D4 which inhibite the adenylclase resulted in the decrease the cAMP. The study between the correlation of DR and Parkinson'disease focused on DRD2 and DRD3. Several polymorphisms had been found in DRD2 including-141C Ins/Del variation in promoter, Taq1A RFLP, (CA)n STR, and three nonsynonymous mutation:Ser311Cys, Pro310Ser, Val96Ala.
Studies have showed that DRD2 TaqIA polymorphism is associated with striatal dopamine D2 receptor density and affect the affinity for substrate. DRD3 gene located in chromosome 3. dopamine receptor D3 gene (DRD3) displays a number of single nucleotide polymorphisms(SNPs), and most frequently studied SNP is the Ser9Gly and MspI RFLP. A report using an in vitro expression system found that the receptors encoded by allele glycine demonstrated a significantly greater affinity for dopamine
Based on these information, our studies aimed to clarify the frequency of OCT2 808G>T in healthy subjects and Parkinson's pations and evaluate the association between OCT2 808G>T mutation and genetic risk for Parkinson's disease. We also investigated the effect of OCT2 808G>T polymorphism on PK of pramipexole and the effect of the common variation of DRD2 and DRD3 on drug response in Parkinson's pation with pramipexole treatment.
The present series studies found that:
1) The frequencies of the OCT 808G>T variant alleles in healthy subjects and Parkinson's pations were 11.4% and 3.1% respectively. The frequencies in Parkinson's pations was significantly lower than in healthy subjects. It demonstrated that there was correlation between OCT2 808G>T mutation and genetic risk for Parkinson's, and the mutation may be a protective factor for Parkinson's disease.
2) To develop a LC-MS/MS method for the determination of pramipexole in human plasma.
3) OCT2 808G>T polymorphism had effect the pharmacokinetics of pramipexole. The Cmax and AUC in subjects carring variant allele were significantly higher than in wild type subjects and the CL/F was significant lower.
4) DRD3 Ser9Gly polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with PD. The response rates for pramipexole treatment was significantly higher in Ser/Ser group (60%) compared with the group containing Gly allel (13%). When the subjects were grouped by DRD2 Taq1A polymorphism, there were no significant differences among three Taq1A genotype. A large-scale and multi-dose group study in patients with parkinson'disease is necessary for evaluating the impact of the genetic polymorphisms of dopamine receptor on therapeutic effects of pramipexole.
In conclusion, our study provide mechanism to the individual differences in drug response of pramipexole from molecular level, healthy subjects level and patientslevel and provided useful information for the clinical use of pramipexole. Before taking pramipexle patients were genotyped for OCT2、DRD2 and DRD3 and would get better therapeutic effect and little adverse reaction.
引文
[1]Polymeropoulos MH, Lavedan C, Leroy E.Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.Science,1997,276(5321):2045-2047.
[2]Kruger R, Kuhn W, Muller T, et al.Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.Nat Genet,1998,18 (2):106-108.
[3]Kitada T, Asakawa S, Hattori N, et al.Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.Nature,1998,392 (6676):605-608.
[4]孔岳南,谢惠君。多巴胺系统基因和帕金森病的相关性。中国临床康复,2003,第7卷第19期：2730-2731.
[5]Gru"ndemann, D., Babin-Ebell, J., Martel, F., O" rding, N., Schmidt, A., and Scho"mig, E. (1997) J. Biol. Chem.272,10408-10413.
[6]Pharmacological and Physiological Functions of the Polyspecific Organic Cation Transporters:OCT1,2, and 3(SLC22A1-3).
[7]Leabman MK, Huang CC, Kawamoto M, et al. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics.2002 Jul; 12(5):395-405.
[8]Fukushima-Uesaka H, Maekawa K, Ozawa S, et al. Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2). Drug Metab Pharmacokinet.2004 Jun; 19(3):239-44.
[9]Lazar A, Zimmermann T, Koch W. Lower prevalence of the OCT2 Ser270 allele in patients with essential hypertension. Clinical and Experimental Hypertension,2006,28: 645-653.
[10]曾丽莉,陈生弟。普拉克索在帕金森病治疗中的临床应用。中国现代神经疾病杂志,2007,7(1)：44-48.
[11]IzumiY, SawadaH, YamamotoN, et al. Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenousd opamine-mediatede xcitotoxicity.E urJ P harmacol,2007,55:132-140.
[12]Lau YY, Hanson GD and Ichhpurani N. Determination of pramipexole (U-98,528) in human plasma and urine by highperformance liquid chromatography with electro-chemical and ultraviolet detection. Journal of Chromatography B 1996a; 683:217.
[13]Nirogi RV, Kandikere V, Shrivastava W, Mudigonda K, Maurya S, Ajjala D.
Quantification of pramipexole in human plasma by liquid chromatography tandem mass spectrometry using tamsulosin as internal standard. Biomed Chromatogr.2007 Nov；21(11):1151-8.
[14]Lau YY, Selenka JM, Hanson GD, Talaat R and Ichhpurani N. Determination of pramipexole (U-98,528) in human plasma by high-performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry. Journal of Chromatography B,1996; 683:209.
[15]Ishiguro N; Saito A; Yokoyama K; Morikawa M; Igarashi T; Tamai I. Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney. Drug Metabolism and Disposition.2005,33:495-499,
[16]Mwinyi J, Johne A, Bauer S, etal. Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 2004; 75:415-21.
[17]Niemi M, Schaeffeler E, Lang T, etal. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C(OATP-C, SLCO1B1). Pharmacogenetics.2004; 14(7):429-440.
[18]Wolkoff, A. W., Goresky, C. A., Sellin, J., etal. Role of ligandin in transfer of bilirubin from plasma into liver. Am J Physiol.1979; 236(6):E 638-48.
[19]ShuY, Brown C, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin. Pharmacol. Ther,2007, 83(2):273-280
[20]Song I., Shin H., Shim E., et al. Genetic Variants of the Organic Cation Transporter 2 Influence the Disposition of Metformin. Clin. Pharmacol. Ther.2008; 100:5902-5907.
[21]Izumi Y, Sawada H, Yamamoto N, Kume T, Katsuki H, Shimohama S, Akaike A. Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity. Eur J Pharmacol.2007 Feb 28;557(2-3):132-40.
[22]Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease:a 4-year randomized controlled trial. Arch Neurol.2004 Jul;61(7):1044-53.
[23]周宏灏主编.遗传药理学.人民军医出版社.
[24]Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of Organic Cation Transporter 2 (OCT2) to Cisplatin-Induced Nephrotoxicity. Clin Pharmacol Ther.2009 Jul 22
[25]Tanihara Y, Masuda S, Katsura T, Inui KI. Protective effect of concomitant administration of imatinib on cisplatin-induced nephrotoxicity focusing on renal organic cation transporter OCT2. Biochem Pharmacol.2009 Jun 18.
[26]Clarke CE, Guttman M (2002) Dopamine agonist monotherapy in Parkinson's disease. Lancet 360(9347):1767-9.
[27]Sokoloff P, Giros B, Martres, MP et al (1990) Molecular cloning and characterization of a novel dopamine receptor (D-3) as a target for neuroleptics. Nature 347:146-151.
[28]Lannfelt L, Sokoloff P, Martres MP et al (1992) Amino acid substitution of the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders. Psychiatr Genet 2:249-256.
[29]Lundstrom K, Turpin MP. Proposed schizophrenia-related gene polymorphism: expression of the Ser/Gly mutant human dopamine D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun.1996;225:1068-1072.
[30]Jonsson EG, Nothen MM, Grunhage F et al (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4(3):290-6.
[31]Wang J, Liu ZL, Chen B et al (2001) Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD. Neurology 56(12):1757-9.
[32]Aklillu E, Kalow W, Endrenyi L et al (2007) CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics 17(11):989-93.
[33]Retz W, Rosler M, Supprian T et al (2003) Dopamine D3 receptor gene polymorphism and violent behavior:relation to impulsiveness and ADHD-related psychopathology. J Neural Transm 110(5):561-72.
[34]Reilly DK, Rivera-Calimlim L, Van-Dyke D (1980) Catechol-O-methyltransferase activity:a determinant of levodopa response. Clin Pharmacol Ther 28(2):278-86.
[35]Rivera-Calimlim L, Reilly DK (1984) Difference in erythrocyte catechol-O-methyltransferase activity between Orientals and Caucasians:difference in levodopa tolerance. Clin Pharmacol Ther 35(6):804-9.
[36]Lee MS, Lyoo CH, Ulmanen I et al (2001) Genotypes of catechol-O-methyltransferase and response to levodopa treatment in patients with Parkinson's disease. Neurosci Lett 298(2):131-4.
[37]Chong DJ, Suchowersky O, Szumlanski C et al (2000) The relationship between COMT genotype and the clinical effectiveness of tolcapone, a COMT inhibitor, in patients with Parkinson's disease. Clin Neuropharmacol 23(3):143-8.
[38]Bialecka M, Drozdzik M, Klodowska-Duda G et al (2004) The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease. Acta Neurol Scand 110(4):260-6.
[39]Contin M, Martinelli P, Mochi M et al (2004) Dopamine transporter gene polymorphism, spect imaging, and levodopa response in patients with Parkinson disease. Clin Neuropharmacol 27(3):111-5.
[40]Skipper L, Liu JJ, Tan EK (2006) Polymorphisms in candidate genes:implications for the current treatment of Parkinson's disease. Expert Opin Pharmacother 7(7):849-55.
[41]Arbouw ME, van Vugt JP, Egberts TC (2007) Pharmacogenetics of antiparkinsonian drug treatment:a systematic review. Pharmacogenomics 8(2):159-76.
[42]Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 2004 Jun;23(6):540-5.
[43]Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park BH, Gauda EB, Lee EJ, Cool MH, Sibley DR, Gerfen CR, Westphal H, Fuchs S. A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci U S A.1996 Mar 5;93(5):1945-9
[1]Pohjalainen T, Rinne JO, Nagren K et.al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers[J]. Mol Psychiatry.1998;3(3):256-60.
[2]Thompson J, Thomas N, Singleton A et.al. D2 dopamine receptor gene (DRD2) TaqI A polymorphism:reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele[J]. Pharmacogenetics.1997;7(6):479-84.
[3]Jonsson EG, Nothen MM, Grunhage F et.al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers[J]. Mol Psychiatry.1999;4(3):290-6.
[4]Jonsson EG, Sillen A, Vares M et.al. Dopamine D2 Receptor Gene Ser311Cys Variant and Schizophrenia:Association Study and Meta-Analysis. Am J Med Genet B Neuropsychiatr Genet[J].2003;119B(1):28-34.
[5]Mant R, Williams J, Asherson P et.al. Relationship between homozygosity at the dopamine D3 receptor gene and schizophrenia[J]. Am J Med Genet.1994;54(1):21-6.
[6]Lundstrom K, Turpin MP. Proposed schizophrenia-related gene polymorphism: expression of the ser9gly mutant humen dopamine D3 receptor with the Semliki Forest virus system[J]. Biochem Biophys Res Commun.1996;225(3):1068-72.
[7]Paus S, Gr(u|¨)newald A, Klein C et.al. The DRD2 TaqlA polymorphism and demand of dopaminergic medication in Parkinson's disease[J]. Mov Disord.2008;23(4):599-602.
[8]Wang J, Liu ZL, Chen B. Dopamine D5 receptor gene polymorphism and the risk of levodopa-induced motor fluctuations in patients with Parkinson's disease [J]. Neurosci Lett.2001;308(1):21-4.
[9]Kaiser R, Hofer A, Grapengiesser A et.al. L-dopa-induced adverse effects in PD and dopamine transporter gene polymorphism[J]. Neurology.2003;60(11):1750-5.
[10]Oliveri RL, Annesi G, Zappia M et.al. Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD[J]. Neurology.1999;53(7):1425-30.
[11]Zappia M, Annesi G, Nicoletti G et.al. Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease:an exploratory study[J]. Arch Neurol.2005;62(4):601-5.
[12]Goetz CG, Burke PF, Leurgans S et.al. Genetic variation analysis in parkinson disease patients with and without hallucinations:case-control study[J]. Arch Neurol.
2001;58(2):209-13.
[13]Heinz A, Goldman D, Jones DW et.al. Genotype influences in vivo dopamine transporter availability in human striatum[J]. Neuropsychopharmacology. 2000;22(2):133-9.
[14]Jacobsen LK, Staley JK, Zoghbi SS et.al. Prediction of dopamine transporter binding availability by genotype:a preliminary report[J]. Am J Psychiatry. 2000;157(10):1700-3.
[15]Contin M, Martinelli P, Mochi M et.al. Dopamine transporter gene polymorphism, spect imaging, and levodopa response in patients with Parkinson'disease[J]. Clin.Neuropharmacol.2004,27(3),111-115.
[16]Lotta T, Vidgren J, Tilgmann C et.al. Kinetics of human soluble and membranebound catechol-O-methyltransferase:a revised mechanism and description of the thermolabile variant of the enzyme[J]. Biochemistry.1995;34(13):4202-10.
[17]Lachman HM, Papolos DF, Saito T et.al. Human catechol-O-methyltransferase pharmacogenetics:description of a functional polymorphism and its potential application to neuropsychiatric disorders[J]. Pharmacogenetics.1996;6(3):243-50.
[18]Reilly DK, Rivera-Calimlim L, Van Dyke D. Catechol-O-methyltransferase activity:a determinant of levodopa response[J]. Clin Pharmacol Ther.1980;28(2):278-86
[19]Rivera-Calimlim L, and Reilly DK., Difference in erythrocyte catechol-O-methyltransferase activity between Orientals and Caucasians:difference in levodopa tolerance[J]. Clin Pharmacol Ther.1984;35(6):804-9.
[20]Chong DJ, Suchowersky O, Szumlanski C et.al. The relationship between COMT genotype and the clinical effectiveness of tolcapone, a COMT inhibitor, in patients with Parkinson's disease[J]. Clin Neuropharmacol'.2000;23(3):143-8.
[21]Nackley AG, Shabalina SA, Tchivileva IE et.al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure [J]. Science.2006;314(5807):1930-3.
[22]Diatchenko L, Slade GD, Nackley AG, et.al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition[J]. Hum Mol Genet. 2005;14(1):135-43.
[23]Bialecka M, Kurzawski M, Klodowska-Duda G et.al. The association of functional catechol-O-methyltransferase haplotypes with risk of Parkinson's disease, levodopa treatment response, and complications [J]. Pharmacogenet Genomics. 2008;18(9):815-21.
[24]Balciuniene J, Emilsson L, Oreland L et.al. Investigation of the functional effect of monoamine oxidase polymorphisms in human brain[J]. Hum Genet.2002;110(1):1-7.
[25]Bialecka M, Drozdzik M, Klodowska-Duda G, et.al.The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease[J]. Acta Neurol Scand. 2004;110(4):260-6.
[26]Zhang F,Xie J X.The protective effects of polysaccharide from spirulina platensis on dopaminergic neurons of MPTP-induced Parkinsons disease model in mice[J]. Chin Pharmacol Bull,2007,23 (9):1241-5.
[27]Niu Y C,Pan Z,Li X M,et al.The protection action of total isoflavones from pueraria lobata against MPP-+induced PC 12 cellular apoptosis[J]. Chin Pharmacol Bull,2009, 25 (1):112-5.
[28]Zhu G Q,Chen Y F,Wang M,et al.The relation between protein degradation pathways and parkinson's disease[J]. Chin Pharmacol Bull,2008,24 (12):1561-4.
[29]Zhao X,Pu X P,Geng X C.Effects of echinacoside on protein expression from substantia nigra and striatal tissue in mouse MPTP model of Parkinsons disease by using 2-dimensional electrophoresis analysis[J]. Chin Pharmacol Bull,2008,24 (1):28-32.
[1]Kim MK and Shim CK. The transport of organic cations in the small intestine:current knowledge and emerging concepts. Arch Pharm Res 2006 (29):605-616
[2]Koepsell H, and Endou H. The SLC22 drug transporter family. Pfliigers Arch, 2004(447):666-676.
[3]Dresser, M.J., Leabman, M.K., and Giacomini, K.M. Transporters involved in the elimination of drugs in the kidney:organic anion transporters and organic cation transporters. J. Pharm. Sci.,2001(90):397-421.
[4]Kerb R, Brinkmann U, Chatskaia N, et al. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics,2002; 12:591-595.
[5]ShuY, Brown C, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin. Pharmacol. Ther,2007, 83(2):273-280.
[6]Susumu Saito, Aritoshi Iida, Akihiro Seki, et al. Catalog of 238 variations among six human genes encoding solute carriers (hSLCs) in the Japanese population. J. Hum Genet,2002(47):576-584.
[7]Takeshi Sakata, Naohiko Anzai, Ho Jung Shin, et al. Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochemical and Biophysical Research Communications,2004(313): 789-793.
[8]Ayako Takeuchi, Hideyuki Motohashi, Masahiro Okuda, et al. Decreased Function of Genetic Variants, Pro283Leu and Arg287Gly, in Human Organic Cation Transporter hOCT1. Drug Metab Pharmacokin,2003,18(6):409-412.
[9]Masaya Itoda, Yoshiro Saito, Keiko Maekawa, et al. Seven Novel Single Nucleotide Polymorphisms in the Huanm SLC22A1 Gene Encoding Organic Cation Transporter 1 (OCT1). Drug Metab. Pharmacokin.2004; 19(4):308-312.
[10]Ho-Jin Kang, Im-Sook Song, Ho Jung Shin, et al. Identification and Functional Characterization of Genetic Variants of Human Organic Cation Transporters in a Korean Population Drug Metab.Dispos.2007; 35(4):667-675.
[11]Shikata E, Yamamoto R, Takane H, et al. Human organic cation transporter (OCT1
and OCT2) gene polymorphisms and therapeutic effects of metformin. J. Hum. Genet.2006; 52:117-122.
[12]Tomoji Maeda, Masanobu Oyabu, Takafumi Yotsumoto, et al. Effect of Pregnane X Receptor Ligand on Pharmacokinetics of Substrates of Organic Cation Transporter Octl in Rats. DRUG METABOLISM AND DISPOSITION 2007; 35:1580-1586.
[13]Tomoji MAEDA, Takafumi YOTSUMOTO, Masanobu OYABU, et al. Effect of Glucocorticoid Receptor Ligand Dexamethasone on the Expression of Organic Cation Transporter in Rat Liver. Drug Metab. Pharmacokinet 2008,23(1):67-72.
[14]Gorboulev V, Ulzheimer JC, Akhoundova A, et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol.1997(16):871-881,.
[15]Leabman MK, Huang CC, Kawamoto M, et al. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics.2002, 12(5):395-405.
[16]Fukushima-Uesaka H, Maekawa K, Ozawa S, et al. Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2). Drug Metab Pharmacokinet.2004 Jun; 19(3):239-44.
[17]Urakami Y,OkudaM, Saito H, et al. Hormonal regulation of organic cation transporter OCT2 exp ression in rat kidney. FEBS Lett 2000; 473 (2):173-176.
[18]Ji L, Masuda S, Saito H, et al. Downregulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int 2002; 62(2):514-524.
[19]Kimura N, Masuda S, Tanihara Y, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1.Drug Metab Pharmacokinet. 2005 Oct; 20(5):379-86.
[20]Dirk Grundemann, Gernot Liebich, Nicholas Kiefer, Sandra Koster. Selective Substrates for Non-Neuronal Monoamine Transporters. Molecular Pharmacology July 1,1999 vol.56 no.11-10.
[21]Grundemann D, Schechinger B, Rappold GA, et al. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nature Neurosci.1: 349-351,1998
[22]Grundemann D, Schomig E. Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Hum. Genet,2000, (106):627-635.
[23]Wu X, Kekuda R, Huang W, et al. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake-2) and evidence for the expression of the transporter in the brain. J Biol Chem,1998(273):32776-32786.
[24]Lazar A, Grundemann D, Berkels R, et al. Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet,2003(48):226-230.
[25]Tamai I.; Yabuuchi H.; Nezu J, et al. Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett.419:107-111,1997.
[26]Tokuhiro S, Yamada R, Chang X, et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nature Genet.35:341-348,2003.
[27]Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genet.2004,36:471-475.
[28]Taubert D, Grimberg G, Jung, N, et al. Functional role of the 503 F variant of the organic cation transporter OCTN1 in Crohn's disease. Gut,2005,54:1505-1506.
[29]Wu X, Prasad PD, Leibach FH, et al. cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem. Biophys. Res. Commun.1998,246:589-595..
[30]Tamai I.; Ohashi R.; Nezu J, et al.Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J. Biol. Chem. 1998,273:20378-20382.
[31]Nezu J, Tamai I, Oku A, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nature Genet. 1999,21:91-94.
[32]Lamhonwah AM, Tein I.Carnitine uptake defect:frameshift mutations in the human plasmalemmal carnitine transporter gene. Biochem. Biophys. Res. Commun.1998,252: 396-401.
[33]Wang Y, Ye J, Ganapathy V, et al. Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency. Proc. Nat. Acad. Sci.1999,96:2356-2360.
[34]Wang Y, Taroni F, Garavaglia B, et al. Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency:lack of genotype-phenotype correlation. Hum. Mutat.2000,16:401-407.
[35]Wang Y, Korman SH, Ye J, et al. Phenotype and genotype variation in primary carnitine deficiency. Genet. Med.2001,3:387-392.
[36]Dobrowolski SF, McKinney JT, di San Filippo CA, et al. Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene. Hum. Mutat.2005,25:306-313.
[37]Tang NLS, Hwu WL, Chan RT, et al. A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients. (Abstract) Hum Mutat.20: 232 only,2002.
[2]Kruger R, Kuhn W, Muller T, et al.Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.Nat Genet,1998,18 (2):106-108.
[3]Kitada T, Asakawa S, Hattori N, et al.Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.Nature,1998,392 (6676):605-608.
[4]孔岳南,谢惠君。多巴胺系统基因和帕金森病的相关性。中国临床康复,2003,第7卷第19期：2730-2731.
[5]Gru"ndemann, D., Babin-Ebell, J., Martel, F., O" rding, N., Schmidt, A., and Scho"mig, E. (1997) J. Biol. Chem.272,10408-10413.
[6]Pharmacological and Physiological Functions of the Polyspecific Organic Cation Transporters:OCT1,2, and 3(SLC22A1-3).
[7]Leabman MK, Huang CC, Kawamoto M, et al. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics.2002 Jul; 12(5):395-405.
[8]Fukushima-Uesaka H, Maekawa K, Ozawa S, et al. Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2). Drug Metab Pharmacokinet.2004 Jun; 19(3):239-44.
[9]Lazar A, Zimmermann T, Koch W. Lower prevalence of the OCT2 Ser270 allele in patients with essential hypertension. Clinical and Experimental Hypertension,2006,28: 645-653.
[10]曾丽莉,陈生弟。普拉克索在帕金森病治疗中的临床应用。中国现代神经疾病杂志,2007,7(1)：44-48.
[11]IzumiY, SawadaH, YamamotoN, et al. Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenousd opamine-mediatede xcitotoxicity.E urJ P harmacol,2007,55:132-140.
[12]Lau YY, Hanson GD and Ichhpurani N. Determination of pramipexole (U-98,528) in human plasma and urine by highperformance liquid chromatography with electro-chemical and ultraviolet detection. Journal of Chromatography B 1996a; 683:217.
[13]Nirogi RV, Kandikere V, Shrivastava W, Mudigonda K, Maurya S, Ajjala D.
Quantification of pramipexole in human plasma by liquid chromatography tandem mass spectrometry using tamsulosin as internal standard. Biomed Chromatogr.2007 Nov；21(11):1151-8.
[14]Lau YY, Selenka JM, Hanson GD, Talaat R and Ichhpurani N. Determination of pramipexole (U-98,528) in human plasma by high-performance liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry. Journal of Chromatography B,1996; 683:209.
[15]Ishiguro N; Saito A; Yokoyama K; Morikawa M; Igarashi T; Tamai I. Transport of the dopamine D2 agonist pramipexole by rat organic cation transporters OCT1 and OCT2 in kidney. Drug Metabolism and Disposition.2005,33:495-499,
[16]Mwinyi J, Johne A, Bauer S, etal. Evidence for inverse effects of OATP-C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics. Clin Pharmacol Ther 2004; 75:415-21.
[17]Niemi M, Schaeffeler E, Lang T, etal. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C(OATP-C, SLCO1B1). Pharmacogenetics.2004; 14(7):429-440.
[18]Wolkoff, A. W., Goresky, C. A., Sellin, J., etal. Role of ligandin in transfer of bilirubin from plasma into liver. Am J Physiol.1979; 236(6):E 638-48.
[19]ShuY, Brown C, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin. Pharmacol. Ther,2007, 83(2):273-280
[20]Song I., Shin H., Shim E., et al. Genetic Variants of the Organic Cation Transporter 2 Influence the Disposition of Metformin. Clin. Pharmacol. Ther.2008; 100:5902-5907.
[21]Izumi Y, Sawada H, Yamamoto N, Kume T, Katsuki H, Shimohama S, Akaike A. Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity. Eur J Pharmacol.2007 Feb 28;557(2-3):132-40.
[22]Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease:a 4-year randomized controlled trial. Arch Neurol.2004 Jul;61(7):1044-53.
[23]周宏灏主编.遗传药理学.人民军医出版社.
[24]Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of Organic Cation Transporter 2 (OCT2) to Cisplatin-Induced Nephrotoxicity. Clin Pharmacol Ther.2009 Jul 22
[25]Tanihara Y, Masuda S, Katsura T, Inui KI. Protective effect of concomitant administration of imatinib on cisplatin-induced nephrotoxicity focusing on renal organic cation transporter OCT2. Biochem Pharmacol.2009 Jun 18.
[26]Clarke CE, Guttman M (2002) Dopamine agonist monotherapy in Parkinson's disease. Lancet 360(9347):1767-9.
[27]Sokoloff P, Giros B, Martres, MP et al (1990) Molecular cloning and characterization of a novel dopamine receptor (D-3) as a target for neuroleptics. Nature 347:146-151.
[28]Lannfelt L, Sokoloff P, Martres MP et al (1992) Amino acid substitution of the dopamine D3 receptor as a useful polymorphism for investigating psychiatric disorders. Psychiatr Genet 2:249-256.
[29]Lundstrom K, Turpin MP. Proposed schizophrenia-related gene polymorphism: expression of the Ser/Gly mutant human dopamine D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun.1996;225:1068-1072.
[30]Jonsson EG, Nothen MM, Grunhage F et al (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4(3):290-6.
[31]Wang J, Liu ZL, Chen B et al (2001) Association study of dopamine D2, D3 receptor gene polymorphisms with motor fluctuations in PD. Neurology 56(12):1757-9.
[32]Aklillu E, Kalow W, Endrenyi L et al (2007) CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics 17(11):989-93.
[33]Retz W, Rosler M, Supprian T et al (2003) Dopamine D3 receptor gene polymorphism and violent behavior:relation to impulsiveness and ADHD-related psychopathology. J Neural Transm 110(5):561-72.
[34]Reilly DK, Rivera-Calimlim L, Van-Dyke D (1980) Catechol-O-methyltransferase activity:a determinant of levodopa response. Clin Pharmacol Ther 28(2):278-86.
[35]Rivera-Calimlim L, Reilly DK (1984) Difference in erythrocyte catechol-O-methyltransferase activity between Orientals and Caucasians:difference in levodopa tolerance. Clin Pharmacol Ther 35(6):804-9.
[36]Lee MS, Lyoo CH, Ulmanen I et al (2001) Genotypes of catechol-O-methyltransferase and response to levodopa treatment in patients with Parkinson's disease. Neurosci Lett 298(2):131-4.
[37]Chong DJ, Suchowersky O, Szumlanski C et al (2000) The relationship between COMT genotype and the clinical effectiveness of tolcapone, a COMT inhibitor, in patients with Parkinson's disease. Clin Neuropharmacol 23(3):143-8.
[38]Bialecka M, Drozdzik M, Klodowska-Duda G et al (2004) The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease. Acta Neurol Scand 110(4):260-6.
[39]Contin M, Martinelli P, Mochi M et al (2004) Dopamine transporter gene polymorphism, spect imaging, and levodopa response in patients with Parkinson disease. Clin Neuropharmacol 27(3):111-5.
[40]Skipper L, Liu JJ, Tan EK (2006) Polymorphisms in candidate genes:implications for the current treatment of Parkinson's disease. Expert Opin Pharmacother 7(7):849-55.
[41]Arbouw ME, van Vugt JP, Egberts TC (2007) Pharmacogenetics of antiparkinsonian drug treatment:a systematic review. Pharmacogenomics 8(2):159-76.
[42]Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 2004 Jun;23(6):540-5.
[43]Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park BH, Gauda EB, Lee EJ, Cool MH, Sibley DR, Gerfen CR, Westphal H, Fuchs S. A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci U S A.1996 Mar 5;93(5):1945-9
[1]Pohjalainen T, Rinne JO, Nagren K et.al. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers[J]. Mol Psychiatry.1998;3(3):256-60.
[2]Thompson J, Thomas N, Singleton A et.al. D2 dopamine receptor gene (DRD2) TaqI A polymorphism:reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele[J]. Pharmacogenetics.1997;7(6):479-84.
[3]Jonsson EG, Nothen MM, Grunhage F et.al. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers[J]. Mol Psychiatry.1999;4(3):290-6.
[4]Jonsson EG, Sillen A, Vares M et.al. Dopamine D2 Receptor Gene Ser311Cys Variant and Schizophrenia:Association Study and Meta-Analysis. Am J Med Genet B Neuropsychiatr Genet[J].2003;119B(1):28-34.
[5]Mant R, Williams J, Asherson P et.al. Relationship between homozygosity at the dopamine D3 receptor gene and schizophrenia[J]. Am J Med Genet.1994;54(1):21-6.
[6]Lundstrom K, Turpin MP. Proposed schizophrenia-related gene polymorphism: expression of the ser9gly mutant humen dopamine D3 receptor with the Semliki Forest virus system[J]. Biochem Biophys Res Commun.1996;225(3):1068-72.
[7]Paus S, Gr(u|¨)newald A, Klein C et.al. The DRD2 TaqlA polymorphism and demand of dopaminergic medication in Parkinson's disease[J]. Mov Disord.2008;23(4):599-602.
[8]Wang J, Liu ZL, Chen B. Dopamine D5 receptor gene polymorphism and the risk of levodopa-induced motor fluctuations in patients with Parkinson's disease [J]. Neurosci Lett.2001;308(1):21-4.
[9]Kaiser R, Hofer A, Grapengiesser A et.al. L-dopa-induced adverse effects in PD and dopamine transporter gene polymorphism[J]. Neurology.2003;60(11):1750-5.
[10]Oliveri RL, Annesi G, Zappia M et.al. Dopamine D2 receptor gene polymorphism and the risk of levodopa-induced dyskinesias in PD[J]. Neurology.1999;53(7):1425-30.
[11]Zappia M, Annesi G, Nicoletti G et.al. Sex differences in clinical and genetic determinants of levodopa peak-dose dyskinesias in Parkinson disease:an exploratory study[J]. Arch Neurol.2005;62(4):601-5.
[12]Goetz CG, Burke PF, Leurgans S et.al. Genetic variation analysis in parkinson disease patients with and without hallucinations:case-control study[J]. Arch Neurol.
2001;58(2):209-13.
[13]Heinz A, Goldman D, Jones DW et.al. Genotype influences in vivo dopamine transporter availability in human striatum[J]. Neuropsychopharmacology. 2000;22(2):133-9.
[14]Jacobsen LK, Staley JK, Zoghbi SS et.al. Prediction of dopamine transporter binding availability by genotype:a preliminary report[J]. Am J Psychiatry. 2000;157(10):1700-3.
[15]Contin M, Martinelli P, Mochi M et.al. Dopamine transporter gene polymorphism, spect imaging, and levodopa response in patients with Parkinson'disease[J]. Clin.Neuropharmacol.2004,27(3),111-115.
[16]Lotta T, Vidgren J, Tilgmann C et.al. Kinetics of human soluble and membranebound catechol-O-methyltransferase:a revised mechanism and description of the thermolabile variant of the enzyme[J]. Biochemistry.1995;34(13):4202-10.
[17]Lachman HM, Papolos DF, Saito T et.al. Human catechol-O-methyltransferase pharmacogenetics:description of a functional polymorphism and its potential application to neuropsychiatric disorders[J]. Pharmacogenetics.1996;6(3):243-50.
[18]Reilly DK, Rivera-Calimlim L, Van Dyke D. Catechol-O-methyltransferase activity:a determinant of levodopa response[J]. Clin Pharmacol Ther.1980;28(2):278-86
[19]Rivera-Calimlim L, and Reilly DK., Difference in erythrocyte catechol-O-methyltransferase activity between Orientals and Caucasians:difference in levodopa tolerance[J]. Clin Pharmacol Ther.1984;35(6):804-9.
[20]Chong DJ, Suchowersky O, Szumlanski C et.al. The relationship between COMT genotype and the clinical effectiveness of tolcapone, a COMT inhibitor, in patients with Parkinson's disease[J]. Clin Neuropharmacol'.2000;23(3):143-8.
[21]Nackley AG, Shabalina SA, Tchivileva IE et.al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure [J]. Science.2006;314(5807):1930-3.
[22]Diatchenko L, Slade GD, Nackley AG, et.al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition[J]. Hum Mol Genet. 2005;14(1):135-43.
[23]Bialecka M, Kurzawski M, Klodowska-Duda G et.al. The association of functional catechol-O-methyltransferase haplotypes with risk of Parkinson's disease, levodopa treatment response, and complications [J]. Pharmacogenet Genomics. 2008;18(9):815-21.
[24]Balciuniene J, Emilsson L, Oreland L et.al. Investigation of the functional effect of monoamine oxidase polymorphisms in human brain[J]. Hum Genet.2002;110(1):1-7.
[25]Bialecka M, Drozdzik M, Klodowska-Duda G, et.al.The effect of monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) polymorphisms on levodopa therapy in patients with sporadic Parkinson's disease[J]. Acta Neurol Scand. 2004;110(4):260-6.
[26]Zhang F,Xie J X.The protective effects of polysaccharide from spirulina platensis on dopaminergic neurons of MPTP-induced Parkinsons disease model in mice[J]. Chin Pharmacol Bull,2007,23 (9):1241-5.
[27]Niu Y C,Pan Z,Li X M,et al.The protection action of total isoflavones from pueraria lobata against MPP-+induced PC 12 cellular apoptosis[J]. Chin Pharmacol Bull,2009, 25 (1):112-5.
[28]Zhu G Q,Chen Y F,Wang M,et al.The relation between protein degradation pathways and parkinson's disease[J]. Chin Pharmacol Bull,2008,24 (12):1561-4.
[29]Zhao X,Pu X P,Geng X C.Effects of echinacoside on protein expression from substantia nigra and striatal tissue in mouse MPTP model of Parkinsons disease by using 2-dimensional electrophoresis analysis[J]. Chin Pharmacol Bull,2008,24 (1):28-32.
[1]Kim MK and Shim CK. The transport of organic cations in the small intestine:current knowledge and emerging concepts. Arch Pharm Res 2006 (29):605-616
[2]Koepsell H, and Endou H. The SLC22 drug transporter family. Pfliigers Arch, 2004(447):666-676.
[3]Dresser, M.J., Leabman, M.K., and Giacomini, K.M. Transporters involved in the elimination of drugs in the kidney:organic anion transporters and organic cation transporters. J. Pharm. Sci.,2001(90):397-421.
[4]Kerb R, Brinkmann U, Chatskaia N, et al. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics,2002; 12:591-595.
[5]ShuY, Brown C, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin. Pharmacol. Ther,2007, 83(2):273-280.
[6]Susumu Saito, Aritoshi Iida, Akihiro Seki, et al. Catalog of 238 variations among six human genes encoding solute carriers (hSLCs) in the Japanese population. J. Hum Genet,2002(47):576-584.
[7]Takeshi Sakata, Naohiko Anzai, Ho Jung Shin, et al. Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochemical and Biophysical Research Communications,2004(313): 789-793.
[8]Ayako Takeuchi, Hideyuki Motohashi, Masahiro Okuda, et al. Decreased Function of Genetic Variants, Pro283Leu and Arg287Gly, in Human Organic Cation Transporter hOCT1. Drug Metab Pharmacokin,2003,18(6):409-412.
[9]Masaya Itoda, Yoshiro Saito, Keiko Maekawa, et al. Seven Novel Single Nucleotide Polymorphisms in the Huanm SLC22A1 Gene Encoding Organic Cation Transporter 1 (OCT1). Drug Metab. Pharmacokin.2004; 19(4):308-312.
[10]Ho-Jin Kang, Im-Sook Song, Ho Jung Shin, et al. Identification and Functional Characterization of Genetic Variants of Human Organic Cation Transporters in a Korean Population Drug Metab.Dispos.2007; 35(4):667-675.
[11]Shikata E, Yamamoto R, Takane H, et al. Human organic cation transporter (OCT1
and OCT2) gene polymorphisms and therapeutic effects of metformin. J. Hum. Genet.2006; 52:117-122.
[12]Tomoji Maeda, Masanobu Oyabu, Takafumi Yotsumoto, et al. Effect of Pregnane X Receptor Ligand on Pharmacokinetics of Substrates of Organic Cation Transporter Octl in Rats. DRUG METABOLISM AND DISPOSITION 2007; 35:1580-1586.
[13]Tomoji MAEDA, Takafumi YOTSUMOTO, Masanobu OYABU, et al. Effect of Glucocorticoid Receptor Ligand Dexamethasone on the Expression of Organic Cation Transporter in Rat Liver. Drug Metab. Pharmacokinet 2008,23(1):67-72.
[14]Gorboulev V, Ulzheimer JC, Akhoundova A, et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol.1997(16):871-881,.
[15]Leabman MK, Huang CC, Kawamoto M, et al. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics.2002, 12(5):395-405.
[16]Fukushima-Uesaka H, Maekawa K, Ozawa S, et al. Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2). Drug Metab Pharmacokinet.2004 Jun; 19(3):239-44.
[17]Urakami Y,OkudaM, Saito H, et al. Hormonal regulation of organic cation transporter OCT2 exp ression in rat kidney. FEBS Lett 2000; 473 (2):173-176.
[18]Ji L, Masuda S, Saito H, et al. Downregulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int 2002; 62(2):514-524.
[19]Kimura N, Masuda S, Tanihara Y, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1.Drug Metab Pharmacokinet. 2005 Oct; 20(5):379-86.
[20]Dirk Grundemann, Gernot Liebich, Nicholas Kiefer, Sandra Koster. Selective Substrates for Non-Neuronal Monoamine Transporters. Molecular Pharmacology July 1,1999 vol.56 no.11-10.
[21]Grundemann D, Schechinger B, Rappold GA, et al. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nature Neurosci.1: 349-351,1998
[22]Grundemann D, Schomig E. Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Hum. Genet,2000, (106):627-635.
[23]Wu X, Kekuda R, Huang W, et al. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake-2) and evidence for the expression of the transporter in the brain. J Biol Chem,1998(273):32776-32786.
[24]Lazar A, Grundemann D, Berkels R, et al. Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3). J Hum Genet,2003(48):226-230.
[25]Tamai I.; Yabuuchi H.; Nezu J, et al. Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett.419:107-111,1997.
[26]Tokuhiro S, Yamada R, Chang X, et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nature Genet.35:341-348,2003.
[27]Peltekova VD, Wintle RF, Rubin LA, et al. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nature Genet.2004,36:471-475.
[28]Taubert D, Grimberg G, Jung, N, et al. Functional role of the 503 F variant of the organic cation transporter OCTN1 in Crohn's disease. Gut,2005,54:1505-1506.
[29]Wu X, Prasad PD, Leibach FH, et al. cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem. Biophys. Res. Commun.1998,246:589-595..
[30]Tamai I.; Ohashi R.; Nezu J, et al.Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J. Biol. Chem. 1998,273:20378-20382.
[31]Nezu J, Tamai I, Oku A, et al. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nature Genet. 1999,21:91-94.
[32]Lamhonwah AM, Tein I.Carnitine uptake defect:frameshift mutations in the human plasmalemmal carnitine transporter gene. Biochem. Biophys. Res. Commun.1998,252: 396-401.
[33]Wang Y, Ye J, Ganapathy V, et al. Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency. Proc. Nat. Acad. Sci.1999,96:2356-2360.
[34]Wang Y, Taroni F, Garavaglia B, et al. Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency:lack of genotype-phenotype correlation. Hum. Mutat.2000,16:401-407.
[35]Wang Y, Korman SH, Ye J, et al. Phenotype and genotype variation in primary carnitine deficiency. Genet. Med.2001,3:387-392.
[36]Dobrowolski SF, McKinney JT, di San Filippo CA, et al. Validation of dye-binding/high-resolution thermal denaturation for the identification of mutations in the SLC22A5 gene. Hum. Mutat.2005,25:306-313.
[37]Tang NLS, Hwu WL, Chan RT, et al. A founder mutation (R254X) of SLC22A5 (OCTN2) in Chinese primary carnitine deficiency patients. (Abstract) Hum Mutat.20: 232 only,2002.