Displaying publications 1 - 20 of 27 in total

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  1. Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT)
    Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.
    Am J Drug Alcohol Abuse, 2016 09;42(5):587-596.
    PMID: 27284701 DOI: 10.3109/00952990.2016.1172078
    BACKGROUND: Methadone is a substrate of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Large interindividual variability in serum methadone levels for therapeutic response has been reported. Genetic variations in ABCB1 gene may be responsible for the variability in observed methadone concentrations.
    OBJECTIVE: This study investigated the associations of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval in opioid-dependent patients on methadone maintenance therapy (MMT).
    METHODS: One hundred and forty-eight male opioid-dependent patients receiving MMT were recruited. Genomic deoxyribonucleic acid (DNA) was extracted from whole blood and genotyped for ABCB1 polymorphisms [i.e. 1236C>T (dbSNP rs1128503), 2677G>T/A (dbSNP rs2032582), and 3435C>T (dbSNP rs1045642)] using the allelic discrimination real-time polymerase chain reaction (PCR). Blood samples were collected at 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the dose. Serum methadone concentrations were measured using the Methadone ELISA Kit.
    RESULTS: Our results revealed an association of CGC/TTT diplotype (1236C>T, 2677G>T/A, and 3435C>T) with dose-adjusted serum methadone concentration over the 24-hour dosing interval. Patients with CGC/TTT diplotype had 32.9% higher dose-adjusted serum methadone concentration over the 24-hour dosing interval when compared with those without the diplotype [mean (SD) = 8.12 (0.84) and 6.11 (0.41) ng ml-1mg-1, respectively; p = 0.033].
    CONCLUSION: There was an association between the CGC/TTT diplotype of ABCB1 polymorphisms and serum methadone concentration over the 24-hour dosing interval among patients on MMT. Genotyping of ABCB1 among opioid-dependent patients on MMT may help individualize and optimize methadone substitution treatment.
    Study site: Psychiatric Clinic, Hospital Universiti Sains Malaysia (HUSM), and other MMT clinics in Kelantan,
    Malaysia
    Matched MeSH terms: P-Glycoproteins/genetics
  2. FZD1 activates protein kinase C delta-mediated drug-resistance in multidrug-resistant MES-SA/Dx5 cancer cells
    Hung TH, Chen CM, Tseng CP, Shen CJ, Wang HL, Choo KB, et al.
    Int J Biochem Cell Biol, 2014 Aug;53:55-65.
    PMID: 24814288 DOI: 10.1016/j.biocel.2014.04.011
    Multidrug-resistant (MDR) cancer is a major clinical problem in chemotherapy of cancer patients. We have noted inappropriate PKCδ hypomethylation and overexpression of genes in the PKCδ/AP-1 pathway in the human uterus sarcoma drug-resistant cell line, MES-SA/Dx5 cells, which also overexpress p-glycoprotein (ABCB1). Recent studies have indicated that FZD1 is overexpressed in both multidrug-resistant cancer cell lines and in clinical tumor samples. These data have led us to hypothesize that the FZD1-mediated PKCδ signal-transduction pathway may play an important role in drug resistance in MES-SA/Dx5 cells. In this work, the PKCδ inhibitor Rottlerin was found to reduce ABCB1 expression and to inhibit the MDR drug pumping ability in the MES-SA/Dx5 cells when compared with the doxorubicin-sensitive parental cell line, MES-SA. PKCδ was up-regulated with concurrent up-regulation of the mRNA levels of the AP-1-related factors, c-JUN and c-FOS. Activation of AP-1 also correlated with up-regulation of the AP-1 downstream genes HGF and EGR1. Furthermore, AP-1 activities were reduced and the AP-1 downstream genes were down-regulated in Rottlerin-treated or PKCδ shRNA-transfected cells. MES-SA/Dx5 cells were resensitized to doxorubicin-induced toxicity by co-treatment with doxorubicin and Rottlerin or PKCδ shRNA. In addition, cell viability and drug pump-out ability were significantly reduced in the FZD1 inhibitor curcumin-treated and FZD1 shRNA-knockdown MES-SA/Dx5 cells, indicating involvement of PKCδ in FZD1-modulated ABCB1 expression pathway. Taken together, our data demonstrate that FZD1 regulates PKCδ, and the PKCδ/AP-1 signalling transduction pathway plays an important role in drug resistance in MES-SA/Dx5 cells.
    Matched MeSH terms: P-Glycoproteins/biosynthesis; P-Glycoproteins/genetics
  3. Relationship Between ABCB1 Polymorphisms and Cold Pain Sensitivity Among Healthy Opioid-naive Malay Males
    Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.
    Pain Pract, 2017 09;17(7):930-940.
    PMID: 27996183 DOI: 10.1111/papr.12546
    BACKGROUND: Endogenous and exogenous opioids are substrates of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Genetic polymorphisms of ABCB1 may contribute to interindividual differences in pain modulation and analgesic responses. We investigated the relationship between ABCB1 polymorphisms and cold pain sensitivity among healthy males.

    METHODS: Cold pain responses, including pain threshold and pain tolerance, were measured using the cold-pressor test (CPT). DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms, including c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642), using the allelic discrimination real-time polymerase chain reaction.

    RESULTS: A total of 152 participants were recruited in this observational study. Frequencies of mutated allele for c.1236C>T, c.2677G>T/A, and c.3435C>T polymorphisms were 56.6%, 49.7%, and 43.4%, respectively. Our results revealed an association of the CGC/CGC diplotype (c.1236C>T, c.2677G>T/A, and c.3435C>T) with cold pain sensitivity. Participants with the CGC/CGC diplotype had 90% and 72% higher cold pain thresholds (87.62 seconds vs. 46.19 seconds, P = 0.010) and cold pain tolerances (97.24 seconds vs. 56.54 seconds, P = 0.021), respectively, when compared with those without the diplotype.

    CONCLUSION: The CGC/CGC diplotype of ABCB1 polymorphisms was associated with variability in cold pain threshold and pain tolerance in healthy males.

    Matched MeSH terms: P-Glycoproteins/genetics
  4. Association of Allelic Interaction of Single Nucleotide Polymorphisms of Influx and Efflux Transporters Genes With Nonhematologic Adverse Events of Docetaxel in Breast Cancer Patients
    Jabir RS, Ho GF, Annuar MABA, Stanslas J
    Clin Breast Cancer, 2018 10;18(5):e1173-e1179.
    PMID: 29885788 DOI: 10.1016/j.clbc.2018.04.018
    PURPOSE: Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients.

    MATERIALS AND METHODS: A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0.

    RESULTS: Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435C>T (P < .05). Moreover, patients carrying the GG genotype of ABCB1 2677G>A/T reported more fatigue than those carrying the heterozygous genotype GA (P < .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P < .05).

    CONCLUSION: The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435C>T polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677G>A/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis.

    Matched MeSH terms: P-Glycoproteins/genetics
  5. ABCB1 Polymorphisms and Cold Pressor Pain Responses: Opioid-Dependent Patients on Methadone Maintenance Therapy
    Zahari Z, Lee CS, Ibrahim MA, Musa N, Mohd Yasin MA, Lee YY, et al.
    Nurs Res, 2017 Mar-Apr;66(2):134-144.
    PMID: 28252574 DOI: 10.1097/NNR.0000000000000204
    BACKGROUND: Methadone is a substrate of the P-glycoprotein efflux transporter, which is encoded by ABCB1 (MDR1), and thus, ABCB1 polymorphisms may influence the transport of methadone at the blood-brain barrier, affecting its adverse effects.

    OBJECTIVES: This study investigated the association between ABCB1 polymorphisms and cold pressor pain responses among opioid-dependent patients on methadone maintenance therapy (MMT).

    METHODS: Malay male opioid-dependent patients receiving MMT (n = 148) were recruited. Cold pressor pain responses (pain threshold, pain tolerance, and pain intensity) were measured at 0, 2, 4, 8, 12, and 24 hours post-methadone dose. DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms including 1236C>T (rs1128503), 2677G>T/A (rs2032582), and 3435C>T (rs1045642) using the allelic discrimination real-time polymerase chain reaction. Repeated-measure analysis of variance between-group analysis was used to compare the three cold pressor pain responses and ABCB1 polymorphisms (1236C>T, 2677G>T/A, and 3435C>T) according to genotypes and allelic additive models, genotype dominant and recessive models, haplotypes, and diplotypes.

    RESULTS: Patients with 2677 GG or 2677G allele had the lowest pain threshold compared with 2677G>T/A genotypes or alleles (p = .007 and .002, respectively). Haplotype analysis showed a significant association between ABCB1 haplotypes and pain threshold (p = .02). Patients with 2677G allele had the lowest pain tolerance compared to those with 2677T and 2677A alleles (2677G < 2677T < 2677A allele carriers; p = .05). In terms of pain intensity scores, patients with 2677 GG or 2677G allele had the highest scores compared to other 2677G>T/A genotypes or alleles (p = .04 and .008, respectively). Haplotype analysis revealed a significant difference between patients with CGC haplotype and those without this haplotype (p = .02).

    DISCUSSION: To the best of our knowledge, this study provides the first evidence that ABCB1 polymorphisms are associated with cold pressor pain responses among Malay male patients with opioid dependence on MMT. The results may provide an initial prediction on heightened pain sensitivity or hyperalgesia for individuals who are carriers of the ABCB1 polymorphisms.
    Matched MeSH terms: P-Glycoproteins/genetics
  6. Knockdown of c-MET induced apoptosis in ABCB1-overexpressed multidrug-resistance cancer cell lines
    Hung TH, Li YH, Tseng CP, Lan YW, Hsu SC, Chen YH, et al.
    Cancer Gene Ther, 2015 May;22(5):262-70.
    PMID: 25908454 DOI: 10.1038/cgt.2015.15
    Inappropriate c-MET signaling in cancer can enhance tumor cell proliferation, survival, motility, and invasion. Inhibition of c-MET signaling induces apoptosis in a variety of cancers. It has also been recognized as a novel anticancer therapy approach. Furthermore, reports have also indicated that constitutive expression of P-glycoprotein (ABCB1) is involved in the HGF/c-MET-related pathway of multidrug resistance ABCB1-positive human hepatocellular carcinoma cell lines. We previously reported that elevated expression levels of PKCδ and AP-1 downstream genes, and HGF receptor (c-MET) and ABCB1, in the drug-resistant MES-SA/Dx5 cells. Moreover, leukemia cell lines overexpressing ABCB1 have also been shown to be more resistant to the tyrosine kinase inhibitor imatinib mesylate. These findings suggest that chemoresistant cancer cells may also develop a similar mechanism against chemotherapy agents. To circumvent clinical complications arising from drug resistance during cancer therapy, the present study was designed to investigate apoptosis induction in ABCB1-overexpressed cancer cells using c-MET-targeted RNA interference technology in vitro and in vivo. The results showed that cell viability decreased and apoptosis rate increased in c-MET shRNA-transfected HGF/c-MET pathway-positive MES-SA/Dx5 and MCF-7/ADR2 cell lines in a dose-dependent manner. In vivo reduction of tumor volume in mice harboring c-MET shRNA-knockdown MES-SA/Dx5 cells was clearly demonstrated. Our study demonstrated that downregulation of c-MET by shRNA-induced apoptosis in a multidrug resistance cell line.
    Matched MeSH terms: P-Glycoproteins/biosynthesis; P-Glycoproteins/genetics
  7. Effects of the ABCB1 C3435T single nucleotide polymorphism on major adverse cardiovascular events in acute coronary syndrome or coronary artery disease patients undergoing percutaneous coronary intervention and treated with clopidogrel: A systematic review and meta-analysis
    Biswas M, Rahaman S, Biswas TK, Ibrahim B
    Expert Opin Drug Saf, 2020 Dec;19(12):1605-1616.
    PMID: 33040624 DOI: 10.1080/14740338.2020.1836152
    INTRODUCTION: The effects of the ABCB1 C3435T genetic polymorphism on clopidogrel responses are conflicting and inconclusive especially in patients undergoing percutaneous coronary intervention (PCI). This study examined the pooled risk of major adverse cardiovascular events (MACE) and bleeding events associated with the ABCB1 C3435T polymorphism in acute coronary syndrome or coronary artery disease patients undergoing PCI and treated with clopidogrel.

    AREAS COVERED: Literature was searched in different resources for eligible studies. The pooled risk ratio was measured using RevMan software, with p<0.05 (two-sided) set as statistically significant.

    EXPERT OPINION: The ABCB1 C3435T homozygous mutant (TT) was associated with significantly increased risk of MACE compared to either wild type genotype (CC) or the combination of wild type and heterozygous genotypes (TT vs. CC: RR 1.33; 95% CI 1.06-1.68; p=0.02; TT vs. CC+CT: RR 1.32; 95% CI 1.10-1.60; p=0.004). Safety outcomes, i.e. bleeding events were not significantly different between the genetic models investigated (TT vs. CC: RR 1.93; 95% CI 0.86-4.35; p=0.11; TT vs. CC+CT: RR 1.36; 95% CI 0.89-2.09; p=0.16; CT+TT vs. CC: RR 1.20; 95% CI 0.59-2.44; p=0.61). It is suggested that ABCB1 C3435T genotype should be tested for ACS/CAD patients undergoing PCI to ensure optimum therapy of clopidogrel.

    Matched MeSH terms: P-Glycoproteins/genetics
  8. Fulltext Pharmacogenomics biomarkers for personalized methadone maintenance treatment: The mechanism and its potential use
    Ramli FF
    Bosn J Basic Med Sci, 2021 Apr 01;21(2):145-154.
    PMID: 32841585 DOI: 10.17305/bjbms.2020.4897
    Methadone has a wide pharmacokinetic interindividual variability, resulting in unpredicted treatment response. Pharmacogenomic biomarkers seem promising for personalized methadone maintenance treatment. The evidence supports the use of ABCB1 single-nucleotide polymorphism (SNP) 1236C>T with genotypes C/T or C/C (Jewish) and haplotypes AGCTT carrier, AGCGC heterozygote, or non-carrier (Caucasian), which have a predicted lower methadone dose requirement. In contrast, ABCB1 SNP 1236C>T with genotype T/T (Jewish); haplotypes AGCGC homozygote, AGCTT non-carrier (Caucasian), and ABCB1 3435C>T variant carrier; and haplotypes CGT, TTC, and TGT (Han Chinese) have a predicted higher methadone dose. For methadone plasma levels, ABCB1 diplotype non-CGC/TTT (Malay) predicted lower, and diplotype CGC/TTT (Malay), 3435C>T allelic carrier, haplotypes (CGT, TTC, TGT) (Han Chinese) predicted higher methadone levels. In terms of metabolism biomarkers, a lower methadone requirement was related to carriers of CYP2B6 genotypes *4(G/G) and *9(T/T) among Jewish patients, CYP2B6*9 genotype (T/T) and haplotypes (TA/TG); and CYP2C19 (*2/*2,*2/*3, and *3/*3; Han Chinese). Higher methadone dose was observed in CYP2C19*1 allelic carriers (Han Chinese) and CYP2D6 ultrarapid metabolizer (Caucasian). Lower methadone levels were reported in CYP2B6 SNPs, haplotypes TTT, and AGATAA (Han Chinese), CYP2C19 genotype *1/*1 (Han Chinese), allelic carrier *1xN (Caucasian), and CYP3A4 genotype *1/*1 (Caucasian). Carriers of CYP2B6 genotype *6/*6 (Caucasian), CYP2B6 haplotypes ATGCAG and ATGCTG (Han Chinese), and CYP3A4 genotype *1/*1B (Caucasian) had predicted higher methadone plasma levels. Specific pharmacokinetics biomarkers have potential uses for personalized methadone treatment in specific populations.
    Matched MeSH terms: P-Glycoproteins/genetics
  9. Association between ABCB1 polymorphism and response to sodium valproate treatment in Malaysian epilepsy patients
    Haerian BS, Lim KS, Tan HJ, Mohamed EH, Tan CT, Raymond AA, et al.
    Epileptic Disord, 2011 Mar;13(1):65-75.
    PMID: 21388909 DOI: 10.1684/epd.2011.0419
    Over-expression of P-glycoprotein, encoded by the ABCB1 gene, is proposed to be involved in resistance to antiepileptic drugs in about 30% of patients with epilepsy. Here, we investigated the possible association between ABCB1 polymorphisms and sodium valproate (VPA) treatment in Malaysian epilepsy patients. Genotypes were assessed in 249 drug-resistant and 256 drug-responsive Malaysian patients for C1236T, G2677T/A, and C 5T polymorphisms in the ABCB1 gene. No genotypes, alleles, or haplotypes were associated with the response to VPA in either the overall group or Chinese, Indian, and Malay subgroups. Our data suggest that C1236T, G2677T/A, and C3435T polymorphisms in the ABCB1 gene do not contribute to the response to VPA in patients with epilepsy.
    Matched MeSH terms: P-Glycoproteins
  10. Fulltext ABCB1 C3435T polymorphism and the risk of resistance to antiepileptic drugs in epilepsy: a systematic review and meta-analysis
    Haerian BS, Roslan H, Raymond AA, Tan CT, Lim KS, Zulkifli SZ, et al.
    Seizure, 2010 Jul;19(6):339-46.
    PMID: 20605481 DOI: 10.1016/j.seizure.2010.05.004
    The C3435T, a major allelic variant of the ABCB1 gene, is proposed to play a crucial role in drug-resistance in epilepsy. The C/C genotype carriers reportedly are at higher risk of pharmacoresistance to AEDs, but only in some studies. The hypothesis of the C-variant associated risk and resistance to antiepileptic drugs (AEDs) has been hampered by conflicting results from inadequate power in case-control studies. To assess the role of C3435T polymorphism in drug-resistance in epilepsy, a systematic review and meta-analysis was conducted.
    Matched MeSH terms: P-Glycoproteins
  11. Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
    Hung TH, Hsu SC, Cheng CY, Choo KB, Tseng CP, Chen TC, et al.
    Oncotarget, 2014 Dec 15;5(23):12273-90.
    PMID: 25401518
    Multidrug resistance in cancer cells arises from altered drug permeability of the cell. We previously reported activation of the Wnt pathway in ABCB1-overexpressed human uterus sarcoma drug-resistant MES-SA/Dx5 cells through active β-catenin and associated transactivation activities, and upregulation of Wnt-targeting genes. In this study, Wnt5A was found to be significantly upregulated in MES-SA/Dx5 and MCF7/ADR2 cells, suggesting an important role for the Wnt5A signaling pathway in cancer drug resistance. Higher cAMP response elements and Tcf/Lef transcription activities were shown in the drug-resistant cancer cells. However, expression of Wnt target genes and CRE activities was downregulated in Wnt5A shRNA stably-transfected MES-SA/Dx5 cells. Cell viability of the drug-resistant cancer cells was also reduced by doxorubicin treatment and Wnt5A shRNA transfection, or by Wnt5A depletion. The in vitro data were supported by immunohistochemical analysis of 24 paired breast cancer biopsies obtained pre- and post-chemotherapeutic treatment. Wnt5A, VEGF and/or ABCB1 were significantly overexpressed after treatment, consistent with clinical chemoresistance. Taken together, the Wnt5A signaling pathway was shown to contribute to regulating the drug-resistance protein ABCB1 and β-catenin-related genes in antagonizing the toxic effects of doxorubicin in the MDR cell lines and in clinical breast cancer samples.
    Matched MeSH terms: P-Glycoproteins/biosynthesis
  12. siRNAs targeting multidrug transporter genes sensitise breast tumour to doxorubicin in a syngeneic mouse model
    Tiash S, Chowdhury EH
    J Drug Target, 2019 03;27(3):325-337.
    PMID: 30221549 DOI: 10.1080/1061186X.2018.1525388
    Chemotherapy, the commonly favoured approach to treat cancer is frequently associated with treatment failure and recurrence of disease as a result of development of multidrug resistance (MDR) with concomitant over-expression of drug efflux proteins on cancer cells. One of the most widely used drugs, doxorubicin (Dox) is a substrate of three different ATP-binding cassette (ABC) transporters, namely, ABCB1, ABCG2 and ABCC1, predominantly contributing to MDR phenotype in cancer. To silence these transporter-coding genes and thus enhance the therapeutic efficacy of Dox, pH-sensitive carbonate apatite (CA) nanoparticles (NPs) were employed as a carrier system to co-deliver siRNAs against these genes and Dox in breast cancer cells and in a syngeneic breast cancer mouse model. siRNAs and Dox were complexed with NPs by incubation at 37 °C and used to treat cancer cell lines to check cell viability and caspase-mediated signal. 4T1 cells-induced breast cancer mouse model was used for treatment with the complex to confirm their action in tumour regression. Smaller (∼200 nm) and less polydisperse NPs that were taken up more effectively by tumour tissue could enhance Dox chemosensitivity, significantly reducing the tumour size in a very low dose of Dox (0.34 mg/kg), in contrast to the limited effect observed in breast cancer cell lines. The study thus proposes that simultaneous delivery of siRNAs against transporter genes and Dox with the help of CA NPs could be a potential therapeutic intervention in effectively treating MDR breast cancer.
    Matched MeSH terms: P-Glycoproteins/genetics
  13. Metronidazole leads to enhanced uptake of imatinib in brain, liver and kidney without affecting its plasma pharmacokinetics in mice
    Tan SY, Kan E, Lim WY, Chay G, Law JH, Soo GW, et al.
    J Pharm Pharmacol, 2011 Jul;63(7):918-25.
    PMID: 21635257 DOI: 10.1111/j.2042-7158.2011.01296.x
    The pharmacokinetic interaction between metronidazole, an antibiotic-antiparasitic drug used to treat anaerobic bacterial and protozoal infections, and imatinib, a CYP3A4, P-glycoprotein substrate kinase inhibitor anticancer drug, was evaluated.
    Matched MeSH terms: P-Glycoproteins/antagonists & inhibitors*
  14. Fulltext Host genetic variants of ABCB1 and IL15 influence treatment outcome in paediatric acute lymphoblastic leukaemia
    Lu Y, Kham SK, Ariffin H, Oei AM, Lin HP, Tan AM, et al.
    Br. J. Cancer, 2014 Mar 18;110(6):1673-80.
    PMID: 24434428 DOI: 10.1038/bjc.2014.7
    Host germline variations and their potential prognostic importance is an emerging area of interest in paediatric ALL.
    Matched MeSH terms: P-Glycoproteins
  15. Fulltext G2677T polymorphism can predict treatment outcome of Malaysians with complex partial seizures being treated with Carbamazepine
    Subenthiran S, Abdullah NR, Muniandy PK, Joseph JP, Cheong KC, Ismail Z, et al.
    Genet. Mol. Res., 2013;12(4):5937-44.
    PMID: 24338387 DOI: 10.4238/2013.November.26.3
    Carbamazepine (CBZ) is used as the first line of treatment of complex partial seizures (CPS) in Malaysia. While this drug is known to be effective for the treatment of CPS, more than 30% of patients remain drug resistant to CBZ mono-therapy. We examined a possible relationship between patients' response to CBZ mono-therapy and the G2677T SNP of the ABCB1 gene. Three hundred and fourteen patients with CPS were recruited from the Neurology Department of the Kuala Lumpur Hospital, of whom 152 were responders and the other 162 were non-responders to CBZ mono-therapy. DNA was extracted from blood samples and real-time PCR was performed to detect the G2677T SNP of the ABCB1 gene. Results were described as genotype frequencies and compared by logistic regression analysis. Among the 152 responders, 74% had the GG genotype. However, among the 162 non-responders, 26.5% had the GT genotype and 39% had the TT genotype. There was a significant difference in genotype frequency (TT vs GG; odds ratio 4.70; 95% confidence interval, 2.70-8.20) between responders and non-responders. The presence of the T allele of the G2677T SNP appears to be a useful screening marker to determine if a patient is going to be resistant to CBZ as a single drug therapy in the treatment of CPS.
    Matched MeSH terms: P-Glycoproteins
  16. Fulltext Linkage disequilibrium between polymorphisms of ABCB1 and ABCC2 to predict the treatment outcome of Malaysians with complex partial seizures on treatment with carbamazepine mono-therapy at the Kuala Lumpur Hospital
    Subenthiran S, Abdullah NR, Joseph JP, Muniandy PK, Mok BT, Kee CC, et al.
    PLoS One, 2013;8(5):e64827.
    PMID: 23717663 DOI: 10.1371/journal.pone.0064827
    Carbamazepine (CBZ) is used as the first line of treatment of Complex Partial Seizures (CPS) in the Epilepsy Clinic, Neurology Department of Kuala Lumpur Hospital (KLH). More than 30% of the patients remain drug resistant to CBZ mono-therapy. CBZ is transported by the P-glycoprotein (P-gp). The P-gp encoded by the ABCB1 and ABCC2 genes are expressed in drug resistant patients with epilepsy. A few studies have shown significant association between CBZ resistant epilepsy and Linkage Disequilibrium (LD) with adjacent polymorphisms of these genes. Our study is aimed at determining the correlation between patients' response to CBZ mono-therapy to Single Nucleotide Polymorphisms G2677T and C3435T of the ABCB1 gene as well as G1249A and -24C>T of the ABCC2 gene.
    Matched MeSH terms: P-Glycoproteins
  17. Fulltext Lack of association of ABCB1 haplotypes on five loci with response to treatment in epilepsy
    Haerian BS, Lim KS, Mohamed EH, Tan HJ, Tan CT, Raymond AA, et al.
    Seizure, 2011 Sep;20(7):546-53.
    PMID: 21530324 DOI: 10.1016/j.seizure.2011.04.003
    Approximately one third of newly treated epilepsy patients do not respond to antiepileptic drugs (AEDs). Overexpression of P-glycoprotein (P-gp) efflux transporter has been proposed to have a critical role in causing resistance to AEDs. P-gp is a product of the ATP-binding cassette subfamily B member 1 (ABCB1) gene. The purpose of this study was to investigate a possible link between ABCB1 rs3789243 C>T, C1236T, G2677T/A, rs6949448 C>T, and C3435T haplotypes with response to carbamazepine (CBZ) or sodium valproate (VPA) monotherapy in Malaysian epilepsy patients. No ABCB1 haplotype association was found with response to either CBZ or VPA monotherapy in the Chinese, Indian, and Malay patients. C3435 allele carriers of the Indian males with cryptogenic epilepsy were more prone to resistance to either CBZ or VPA than carriers of T allele. Moreover, rs3789243T allele carriers of Malay females with symptomatic epilepsy were more resistant to either CBZ or VPA than C allele carriers. Our findings suggest that the ABCB1 rs3789243 C>T, C1236T, G2677T/A, rs6949448 C>T, and C3435T haplotypes do not contribute to response to AED treatment in epilepsy.
    Matched MeSH terms: P-Glycoproteins
  18. Association of ABCB1 gene polymorphisms and their haplotypes with response to antiepileptic drugs: a systematic review and meta-analysis
    Haerian BS, Lim KS, Tan CT, Raymond AA, Mohamed Z
    Pharmacogenomics, 2011 May;12(5):713-25.
    PMID: 21391884 DOI: 10.2217/pgs.10.212
    Several studies demonstrated a link between ABCB1 gene variants and the response to treatment in epilepsy, but the results have been inconclusive. Here, we performed the first haplotype meta-analysis to examine the association of haplotypes of ABCB1 common variants with the response to treatment in epilepsy.
    Matched MeSH terms: P-Glycoproteins
  19. Fulltext The risk of recurrence in breast cancer patients treated with tamoxifen: polymorphisms of CYP2D6 and ABCB1
    Teh LK, Mohamed NI, Salleh MZ, Rohaizak M, Shahrun NS, Saladina JJ, et al.
    AAPS J, 2012 Mar;14(1):52-9.
    PMID: 22183189 DOI: 10.1208/s12248-011-9313-6
    CYP2D6 plays a major role in the metabolism of tamoxifen, and polymorphism of P-glycoprotein has been associated with resistance of many drug therapies. This study investigates the clinical impact of genetic variants of CYP2D6 and ABCB1 in breast cancer patients treated with tamoxifen. Blood samples from 95 breast cancer patients treated with tamoxifen were collected and genotyped for CYP2D6 and ABCB1 variants using allele-specific PCR method. Recurrence risks were calculated using Kaplan-Meier analysis and compared using the log-rank test. Patients carrying CYP2D6*10/*10 and heterozygous null allele (IM) showed higher risks of developing recurrence and metastasis (OR 13.14; 95% CI 1.57-109.94; P = 0.004) than patients with CYP2D6*1/*1 and *1/*10 genotypes. Patients with homozygous CC genotypes of ABCB1 C3435T showed a shorter time to recurrence. Patients who were CYP2D6 IM and homozygous CC genotype of C3435T have statistically significant higher risks of recurrence (P = 0.002). Similarly, median time to recurrence in these patients was only 12 months (95% CI = 0.79-23.2) compared to those without this combination which was 48 months (95% CI = 14.7-81.2). Patients with CYP2D6 IM and homozygous CC genotype of ABCB1 C3435T have shorter times to recurrence. The results confirmed the findings of previous studies and support FDA recommendation to perform pre-genotyping in patients before the choice of therapy is determined in breast cancer patients.
    Matched MeSH terms: P-Glycoproteins
  20. Pharmacogenotyping of CYP3A5 in predicting dose-adjusted trough levels of tacrolimus among Malaysian kidney-transplant patients
    Hamzah S, Teh LK, Siew JS, Ahmad G, Wong HS, Zakaria ZA, et al.
    Can J Physiol Pharmacol, 2014 Jan;92(1):50-7.
    PMID: 24383873 DOI: 10.1139/cjpp-2013-0128
    Tacrolimus (FK506) is a calcineurin inhibitor with a narrow therapeutic index that exhibits large interindividual variation. Seventy-eight kidney transplant patients treated with tacrolimus were recruited to study the correlation of dose adjusted trough level (level/dose; L/D) of tacrolimus with CYP3A5 and ABCB1 genotypes, as well as the mRNA copy number of ABCB1 in blood. Patients were genotyped for ABCB1 (C1236T, G2677T/A, and C3435T) and CYP3A5 (G6986A), while ABCB1 mRNA transcript copy number was determined by absolute quantification (real-time PCR) in 46 patients. CYP3A5*3 genotypes were found to be a good predictor of tacrolimus L/D in kidney-transplant patients. Significantly higher L/D was observed among non-expressors (2.85, 95%: 2.05-3.70 (ng·mL(-1))/(mg·kg(-1))) as compared with the expressors (1.15, 95%: 0.95-1.80 (ng·mL(-1))/(mg·kg(-1))) of CYP3A5 (Mann-Whitney U test; P < 0.001). No correlation was observed between L/D and the ABCB1 genotypes. A significant inverse correlation of blood ABCB1 mRNA level with L/D was demonstrated (Spearman's Rank Order correlation; P = 0.016, rs = -0.348). However, in multiple regression analysis, only CYP3A5*3 genotype groups were found to be significantly correlated with tacrolimus L/D (P < 0.001). These findings highlight the importance of CYP3A5*3 pharmacogenotyping among kidney-transplant patients treated with tacrolimus, and confirm the role of blood cell P-glycoprotein in influencing the L/D for tacrolimus.
    Matched MeSH terms: P-Glycoproteins
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