难治性癫痫与多药耐药基因1C3435T多态性的相关性

目的 探讨多药耐药基因1(MDR1)C3435T位点多态性与汉族难治性癫痫(RE)的关系. 方法 收集170例诊断明确、治疗合理的汉族癫痫患者,根据是否符合RE诊断标准将其分为RE组(91例)和非RE组(79例).RE定义为:至少观察2年,按患者发作类型正确使用≥2种对该发作类型有效的抗癫痫药物,单药前、后分别使用或联合使用,仍每月发作≥1次达2年及以上者.采用多聚酶链反应限制性片段长度多态性方法检测患者外周血MDR1基因C3435T多态性. 结果 RE组CC、CT、TT基因型分别占48.4%、40.7%、11.0%,非RE组分别占40.5%、38.0%、21.5%,总体差异无统计学意义(x2=3.615,P=0.164).RE组患者C3435T等位基因C、T频率分别为68.7%、31.3%,非RE组患者分别为59.5%、40.5%,差异也无统计学意义(x2=3.112,P=0.080).根据病因将患者分为原发性癫痫、症状性或隐源性癫痫2组,结果示2组患者中RE亚组和非RE亚组C3435T基因型分布、等位基因频率差异均无统计学意义(P＞0.05). 结论 本研究未发现MDR1基因C3435T多态性与汉族RE有关.

Abstract：

Objective To clarify the relation between the C3435T polymorphism of multidrug resistance 1 (MDR1) gene and human refractory epilepsy (RE) in ethnic Han Chinese. Methods We collected 170 patients with epilepsy, whose diagnoses were correct and treatments were reasonable. RE was defined as having uncontrolled seizures that occurred with an average frequency of at least once a month for a period of at least 2 years; during the 2-years period, at least 2 different antiepileptic drugs (AEDs) were used daily, either singly or in combination. According to the definition, 91 patients were classified into RE group and the other 79 patients into non-RE group. A 5-mL venous blood sample was taken from the patients for DNA extraction and genotyping. Genotype of C3435T polymorphism in MDR1 gene was determined by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). Results The distribution of CC, CT, TT genotypes was 48.4%, 40.7%,11.0% in RE group, and 40.5%, 38.0%, 21.5% in non-RE group, respectively; no significant differences of C3435T genotype were noted between the 2 groups (x2=3.615, P=0.164). The C and T allele frequencies were 68.7%, 31.3% in RE group, and 59.5%, 40.5% in non-RE group, respectively; no significant differences were found between 2 groups (x2=3.112, P=0.080). Patients were divided into primary epilepsy group and cryptogenic or symptomatic epilepsy group according to the etiology;analyses of the genotype and allele of C3435T in the sub-groups (RE and non-RE subgroups) of this 2 groups were similarly unremarkable. Conclusion No association between the C3435T polymorphism in MDR1 gene and RE in ethnic Han Chinese is noted.     

Association of MDR1 gene C3435T polymorphism with childhood intractable epilepsy: a meta-analysis

Drug-resistant epilepsy is also referred to as intractable, medically refractory, or pharmacoresistant epilepsy. Approximately, one-third of patients with epilepsy have recurrent seizures despite therapy. Multidrug resistance 1 (MDR1) gene may play a role in drug-resistance in epilepsy. To assess the association between MDR1 C3435T polymorphism and the response to anticonvulsants in childhood intractable epilepsy, we conducted a systematic review and meta-analysis. Studies were obtained from the electronic database of PubMed, Medline, Embase and CNKI up to September 2013. All the case–control association researches evaluating the role of MDR1 C3435T polymorphism in childhood epilepsy to antiepileptic drugs were identified. The odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated for comparisons of the alleles and genotypes with co-dominant (C/C vs. T/T, C/T vs. T/T), dominant (C/C + C/T vs. T/T), and recessive (C/C vs. C/T + T/T) models in overall and in ethnicity subgroups to measure the strength of genetic association. A total of 8 related studies, including 634 drug-resistant patients, 615 drug-responsive patients and 1,052 healthy controls were pooled in this meta-analysis. The allelic association of MDR1 C3435T with risk of drug-resistance was not significant (OR 1.03, 95 % CI 0.87–1.22, P = 0.73; OR 1.00, 95 % CI 0.86–1.16, P = 0.98) in overall and in the subgroup analysis by ethnicity (Asian: OR 0.95, 95 % CI 0.77–1.18, P = 0.67; Caucasian: OR 1.18, 95 % CI 0.89–1.57, P = 0.25). Neither association was found in other genetic models. Our results did not show a significant association between MDR1 C3435T polymorphism and response to anticonvulsant drugs, suggesting that this polymorphism may not be a risk factor to childhood intractable epilepsy.     

Single nucleotide polymorphisms in the multidrug resistance 1 gene in Korean epileptics.

PURPOSE: P-glycoprotein 170 encoded by the multidrug resistance 1 (MDR1) gene exports various antiepileptic drugs out of the CNS, which leads to multidrug resistance. This study was performed to elucidate the relationship between single nucleotide polymorphisms (SNPs) in the MDR1 gene and drug resistance in Koreans with epilepsy. SUBJECTS AND METHODS: Three SNPs at nucleotide position 1236 in exon 12, 2677 in exon 21 and 3435 in exon 26 of the MDR1 gene were genotyped in 207 Korean epileptics. Subjects were classified according to whether they had drug-resistant (RS group; N=99) or drug-responsive epilepsy (RP group; N=108). The frequencies of genotype and haplotype were compared between the RS and RP groups. RESULTS: The frequencies of genotype and haplotype in the RS group were not statistically different from those in the RP group. CONCLUSIONS: In Korean epileptics, there was no significant relationship between three known SNPs in MDR1 and drug resistance. And there was no association of MDR1 haplotype based on above three sites with pharmacoresistance.     

Associations between <Emphasis Type="Italic">MDR1</Emphasis> C3435T polymorphism and drug-resistant epilepsy in the Polish population

Epilepsy is a common neurological disorder. About one-third of epileptic patients demonstrate multidrug resistance (MDR) phenotype and develop drug-resistant epilepsy (DRE). Single nucleotide polymorphism (SNP) C3435T (rs1045642), identified in the MDR1 gene, is associated with an increased intestinal expression of P-glycoprotein (P-gp) which affects the levels of anti-epileptic drugs in plasma. The reported study was designed to explore associations between the MDR1-C3435T gene SNP and the risk of DRE in the Polish population. The C3435T polymorphism of MDR1 gene was investigated by the PCR-RFLP technique in 74 patients with DRE and 70 age- and sex-matched non-DRE controls. Blood samples were obtained from patients with drug-resistant epilepsy, treated at the Department of Neurological Surgery, Medical University in Warsaw between the years 2011 and 2012. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for each genotype and allele. Genotype distribution of C3435T polymorphism of MDR1 gene was compared between the DRE patients and controls with significant differences (p < 0.05) between the two investigated groups. A possible association was observed between DRE and the presence of 3435C allele. The 3435C allele was found in 69 % of DRE cases and in 48 % of the used controls. The variant 3435T allele of MDR1 decreased the risk of drug-resistant epilepsy [odds ratio (OR) 0.41; 95 % confidence interval (CI) 0.26–0.67]. The results indicate that the C3435T polymorphism of MDR1 gene may be associated with the incidence of DRE observed in the Polish population.     

Lack of association between C3435T nucleotide MDR1 genetic polymorphism and multidrug-resistant epilepsy.

The variability of P-glycoprotein expression in individuals is linked to a C3435T polymorphism of the multidrug-resistance 1 (MDR1) gene, and the CC genotype at the C3435T polymorphism was reported to be associated with multidrug resistance in epilepsy patients. Since population frequencies of polymorphic genes depend on ethnic specificity, we investigated functional significance of the C3435T polymorphism of the MDR1 gene in Korean epilepsy patients. One hundred and eight patients with drug-responsive epilepsy, 63 patients with drug-resistant epilepsy, and 219 control migraine subjects were studied, but the analysis for C3435T allele showed no significant association between the CC genotype and the multidrug-resistant epilepsy. We suggest that influence of the C3435T polymorphism in the multidrug-resistant epilepsy may not be significant in Korean populations and further investigations in various ethnic populations would be necessary to clarify the effect of C3435T polymorphism on the mutidrug resistance in epilepsy patients.     

Effects of ABCB1 polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy

P-glycoprotein may play a role in drug resistance in epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs (AEDs). We sought to investigate the effects of ABCB1 polymorphisms on plasma carbamazepine (CBZ) concentrations and pharmacoresistance in Chinese patients with epilepsy. C1236T, G2677T/A, and C3435T polymorphisms of ABCB1 were genotyped by polymerase chain reaction amplification followed by restriction fragment length polymorphism analysis or direct automated DNA sequencing in 84 patients treated with CBZ monotherapy. Patients with 3435-TT (n=15) had lower adjusted CBZ concentrations than those with 3435-CC (n=30) (P=0.026). However there were no associations between all the studied genotypes, haplotypes, or diplotypes involving ABCB1 C1236T, G2677T/A, and C3435T polymorphisms and pharmacoresistance in the patient cohort. Our results suggest that ABCB1 3435-TT is associated with decreased plasma CBZ levels in Chinese patients with epilepsy. However, whether this contributes to CBZ resistance needs to be further investigated in a larger cohort of patients.     

Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment

PURPOSE: P-glycoprotein (P-gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P-gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). Recent evidence suggests that the homozygous C-variant, which is associated with higher expression and increased activity of P-gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic. METHODS: DNA samples were obtained from 400 patients, irrespective of seizure type or drug treatment. Genotype of the C3435T polymorphism was determined by traditional polymerase chain reaction (PCR) followed by restriction digest. Classification of response to treatment was determined in a blinded fashion by an independent physician. Results were expressed as genotype and allele frequencies per response group and compared by logistic regression analysis. RESULTS: In total, 170 patients were classified as responders, with > or =12 months seizure freedom on current treatment. The remaining 230 patients were classified as nonresponders. Comparison of responders and nonresponders revealed no significant difference in allele frequency (C vs. T; odds ratio, 1.03; 95% CI, 0.78-1.37; p = 0.83) or genotype frequency (CC vs TT; odds ratio, 1.07; 95% CI, 0.60-1.91; p = 0.81). Subanalyses of individual seizure types were similarly unremarkable. CONCLUSIONS: This study failed to corroborate a previously reported association between the C3435T polymorphism in the human MDR1 gene and pharmacoresistant epilepsy. Whether the C3435T polymorphism can act as a marker for the natural history of treated epilepsy remains to be determined.     

MDR1C3435T基因多态性与抗癫痫药卡马西平疗效的相关性研究

目的研究癫痫患者外周血中MDR1(多药耐药)C3435T位点基因分型,分析C3435T基因多态性与患者血药浓度及疗效的相关性。方法收集服用卡马西平的癫痫患者80例,根据疗效分为有效组和耐药组,同时测定其血药浓度;采用PCR-RFLP(聚合酶链反应-限制性片段长度多态性分析)技术检测其MDR1C3435T位点的基因型。将有效组和耐药组的CBZ血药浓度及基因型进行比较。结果有效组与耐药组基因型进行χ2检验(χ2=2.825,P=0.244),无统计学差别。结论MDR1C3435T基因多态性与抗癫痫药CBZ的血药浓度及疗效没有明显相关性。     

The effect of MDR1 gene polymorphism in the pathogenesis and the treatment of drug-resistant epilepsy

Recent data indicate the possibility of P-glycoprotein involvement in drug resistance in patients diagnosed with epilepsia. It was demonstrated that P-glycoprotein is expressed in the endothelial cells of the blood-brain barrier, and in neurons and glial cells isolated from the epileptogenic brain tissue. The glycoprotein functions as an efflux pump, thus limiting penetration of antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, gabapentin, felbamate, topiramate, lamotrigine) to the site of action. A naturally occurring MDR1 polymorphism has been described and correlated with potential clinical effects. The C3435T polymorphism was found to significantly correlate with the function of MDR1 and the expression of P-glycoprotein. This polymorphism consists of a C-to-T exchange at position 3435 in exon 26 of the MDR1 gene. Individuals with the TT genotype had significantly lower P-glycoprotein expression than those with the CC and CT genotype. Because C3435T does not change the amino acid sequence and is not located at a promotor position in the MDR1 gene, it is unlikely that this polymorphism directly influences P-glycoprotein expression. However, a strong association between the C3435T and G2677 (A, T) allele was revealed. Since G2677 (A, T) in exon 21 is a missense mutation, it is likely to be causative for differences in P-glycoprotein expression. Finding out the relationship between MDR-1 gen polymorphism and drug-resistant epilepsia may lead to the effective treatment of epilepsia by application of P-glycoprotein inhibitors.     

No association of ABCB1 polymorphisms with drug-refractory epilepsy in a north Indian population

Multiple drug resistance is a common problem in the treatment of epilepsy, and approximately 30% of patients continue to have seizures despite all therapeutic interventions. Among various classes of drug transporters, genetic variants of P-glycoprotein (P-gp) encoded by the ABCB1 (ATP-binding cassette subfamily B member 1) gene have been associated with drug-refractory epilepsy. Our aim was to investigate the effect of the 1236C>T(rs1128503), 2677G>T/A(rs2032582), and 3435C>T(rs1045642) single-nucleotide polymorphisms of ABCB1 (or MDR1) on drug resistance in north Indian patients with epilepsy. Genotyping was performed in 101 control subjects and 325 patients with epilepsy, of whom 94 were drug resistant and 231 drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital, and valproate was also performed to confirm compliance in 20% of the patients. Genotype and haplotype frequencies of these polymorphisms did not differ between drug-resistant and drug-responsive patients. Our results demonstrate ABCB1 polymorphisms are not associated with drug resistance in north Indian epileptic patients.     

Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy

Intractable seizures are the most common manifestation in severe cases of tuberous sclerosis. Multidrug resistance type 1 (MDR1) gene expression is directly linked to the resistance of tumor cells to chemotherapy as the major cause of treatment failure, but it has not been reported in tuberous sclerosis cells nor has the relationship between the MDR1 gene and antiepileptic drugs been described. A 4-month-old female is described with poorly controlled seizures secondary to tuberous sclerosis. The patient was treated with antiepileptic drugs, including phenytoin, phenobarbital, and lorazepam, without improvement of symptoms. Phenytoin blood levels were invariably subtherapeutic and ranged from 0.45 to 3.55 microg/mL, despite several consecutive intravenous loading doses. Surgical treatment with total resection of the brain lesions was performed as a last resort. Immunohistochemical analysis of the resected tissues revealed high levels of P-glycoprotein 170 expression, the product of the MDR1 gene. Both MDR1 gene expression and persistently low phenytoin levels likely share a common pathway liable to induce drug-resistant epilepsy.     

Multidrug-resistant genotype (ABCB1) and seizure recurrence in newly treated epilepsy: Data from international pharmacogenetic cohorts

Purpose:   The association between a specific polymorphism ( 3435C > T ) in the ABCB1 gene, coding for the membrane drug transporter P-glycoprotein (PgP), and pharmacoresistance to seizure control is controversial. Studies have been limited by multiple drug use, chronic cohorts with varying definitions, and retrospective clinical data. Herein we examine the relationship of this polymorphism with seizure recurrence in three independent international cohorts of patients newly treated for epilepsy.
Methods:   Data were collected on demographics, medication details, and seizure control after 12 months of treatment. The distribution of ABCB1 3435C>T genotypes was compared between patients with and without recurrent unprovoked seizures.
Results:   Five hundred forty-two newly treated patients were enrolled (212 from Australia, 285 from Scotland, and 45 from Hong Kong). A total of 38.4% had recurrent unprovoked seizures after starting antiepileptic drug (AED) treatment. Genotype frequencies and ethnicity did not differ between the Scottish and Australian cohorts, but both were significantly different in the Hong Kong cohort. There was no significant relationship between the ABCB1 3435C > T genotype and the rate of recurrence of unprovoked seizures in the three cohorts individually or combined; however the epilepsy syndrome and a greater number of seizures pretreatment was associated with an increased risk of seizure recurrence.
Conclusions:   The ABCB1 3435C > T genotype does not have a major role in determining the efficacy of seizure control with initial AED therapy. The study highlights issues that arise in combining pharmacogenetic datasets from different ethnic regions and health systems, an approach that is essential to advance this field.     

Polymorphism of the MDR1/ABCB1 C3435T drug-transporter and resistance to anticonvulsant drugs: A meta-analysis

Background:   Approximately one-third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug-transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system.
Methods:   We conducted a meta-analysis to examine the association between MDR1 polymorphisms and the response to anticonvulsants. We included all published studies until September 2007, in which patients with responsive and unresponsive seizure disorders underwent genotyping for ABCB1 C3435T. Individual and summary odds ratios were calculated using a random effects model. A secondary analysis was also performed, stratifying the studies by their ethnic distribution to account for genetic heterogeneity. We also performed a cumulative analysis by date of publication for the included studies using a random effects model.
Results:   We identified 11 case-control studies involving 3,371 patients (1,646 patients with drug-resistant epilepsy and 1,725 controls). We identified no significant association between anticonvulsant drug resistance and MDR1 polymorphism [odds ratio 1.15; 95% confidence interval (CI) 0.78–1.70; p = 0.48). Subanalysis of studies according to ethnicity yielded similar findings [European cohort: OR = 1.31; 95% CI 0.89–1.94, p = 0.18; Asian cohort: OR = 0.99; 95% CI 0.51–1.89, p = 0.96).
Conclusions:   We found no association between ABCB1 genotype and response to anticonvulsant drugs. At the present time, genetic typing for MDR1 polymorphism is not warranted for patients with drug-resistant epilepsy.     

Effect of MDR1 haplotype on risk of Parkinson disease

BACKGROUND: MDR1, a multidrug transporter, encodes a P-glycoprotein that regulates the bioavailability of xenobiotics and is highly expressed at the blood-brain-barrier. Two single nucleotide polymorphisms (SNPs) (e21/2677[G/T/A] and e26/3435[C/T]) in the MDR1 gene can lead to differences in MDR1 expression and function. Specific MDR1 alleles of the 2 SNPs are positively selected among ethnic Chinese but not in the white population. OBJECTIVE: To determine whether specific haplotypes formed by SNPs e21/2677 and e26/3435 may protect against Parkinson disease (PD) among ethnic Chinese in Hong Kong. DESIGN: Case-control study. SETTING: Tertiary referral centers in Hong Kong. SUBJECTS: One hundred eighty-five patients with PD and 206 control subjects. INTERVENTIONS: The two SNPs were amplified in a single multiplex polymerase chain reaction. Five other SNPs that span 100 kilobases of the gene were also analyzed. MAIN OUTCOME MEASURES: Haplotypes frequencies, degree of haplotype association with the disease status, and estimated odds ratio for each haplotype with associated 95% confidence intervals. RESULTS: In addition to 2677 G-->T/A (exon 21) and 3435 C-->T (exon 26), the other SNPs that were analyzed were -41 A-->G (intron -1), -145 C-->G (exon 1), -129 T-->C (exon 1), 1236 T-->C (exon 12), and 4036 A-->G (exon 28). Haplotypes containing SNPs e21/2677 and e26/3435 were found to be significantly associated with risk of PD. In particular, the 2677T-3435T haplotype was strongly associated with a reduced risk of PD (P<.001; chi(2) = 14.521; odds ratio, 0.33; 95% confidence interval, 0.19-0.59). CONCLUSIONS: An MDR1 haplotype containing SNPs e21/2677T and e26/3435T protects against PD in ethnic Chinese, compatible with the observation of a recent positive selection of the T alleles of these 2 SNPs in this ethnic population.     

The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >/=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >/=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >/=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.     

Association between MDR1 C3435T polymorphism and refractory epilepsy in the Chinese population: A systematic review and meta-analysis

The association between the C3435T polymorphism in the MDR1 gene and refractory epilepsy remains controversial. The association appears to be influenced by ethnicity and region. We have performed a systematic review and meta-analysis to assess the link between the MDR1 C3435T polymorphism and refractory epilepsy in the Chinese population. We searched the Cochrane Library, MIDLINE, EMBASE, CBM disc, CNKI, VIP, and WANFANG databases for literature published through August 2013 for case–control studies that evaluated the association between the MDR1 C3435T polymorphism and refractory epilepsy. Twenty-one case–control studies involving 4269 patients (1863 cases in the group with drug-resistant epilepsy and 2406 in the group with drug-responsive epilepsy) were included in the systematic review and meta-analysis. The analysis showed that there were significantly more cases with the MDR1 3435 CC genotype in the group with drug-resistant epilepsy than in the group with drug-responsive epilepsy [odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.09–2.06, P = 0.01]. In a subanalysis of patients from the southern regions of China, the correlation was not significant [odds ratio (OR) = 1.2, 95% confidence interval (CI) = 0.89–1.64, P = 0.24]. The relationship established in a subset of the Chinese population between the MDR1 C3435T polymorphism and refractory epilepsy will guide epilepsy treatment and development of new AEDs.     

Association between multidrug resistance 1 (MDR1) gene polymorphisms and therapeutic response to bromperidol in schizophrenic patients: a preliminary study

The drug-transporting P-glycoprotein transports drugs against a concentration gradient across the blood-brain barrier back into the plasma and thereby reduces the bioavailability in the brain. Polymorphisms in the MDR1 gene regulating P-glycoprotein expression can be associated with differences in drug disposition in the brain. The present study was therefore designed to examine whether the major polymorphisms of MDR1 gene, C3435T and G2677T/A are related to therapeutic response to neuroleptics in the treatment of schizophrenia. Subjects consisted of 31 acutely exacerbated schizophrenic inpatients treated with bromperidol (6-18 mg/day). Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The C3435T and G2677T/A genotypes were determined by a polymerase chain reaction method. Schizophrenic symptoms were allocated into 5 clusters: positive, excitement, cognitive, negative, and anxiety-depression symptoms. Patients were C/C in 12, C/T in 12 and T/T in 7 cases for C3435T genotype and G/G in 3, G/T or A in 17 and T or A/T or A in 11 cases for G2677T/A genotype. There were a tendency of difference, but not statistically different, in the percentage improvement or the improved scores of 5 sub-grouped symptoms after the 3-week treatment between C3435T genotypes and between G2677T/A genotypes. Multiple regression analyses including age, body weight, gender and drug concentration showed significant correlations between the percentage improvement and the improved scores of cognitive symptoms and C3435T genotypes. The present results suggest that the C3435T polymorphism is associated with some therapeutic response to bromperidol in schizophrenic patients, possibly by different drug concentration in the brain.     

MDR1 gene polymorphism: therapeutic response to paroxetine among patients with major depression

The multidrug resistance transporter, P-glycoprotein (P-gp), encoded by polymorphic MDR1 (ABCB1) gene, is involved in efflux transport of several antidepressants and acts as a barrier to different exogenous noxa in the blood-brain barrier. MDR1 gene belongs to the best understood mediators of drug resistance. Different polymorphisms in MDR1 have been found to be connected with P-gp expression and function. The aims of the study were to investigate the potential influence of MDR1 polymorphisms, exon 26 C3435T and exon 21 G2677T/A, on treatment response to paroxetine (20 mg/day) in patients with major depression. To assess and evaluate therapeutic response to paroxetine, all patients were rated weekly using the HAMD-17 scale. Responders were defined as subjects with a decrease in HAMD scale by >or=50% at week 6 of treatment. The study population included 127 patients with major depression (diagnosed by Structured Clinical Interview for DSM-IV disorders). Our results indicated that MDR1 variants G2677T and C3435T are not associated with therapeutic response to paroxetine in patients with major depressive disorder. The associations between paroxetine and P-glycoprotein still need to be clarified.