Displaying publications 1 - 20 of 30 in total

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  1. [Prevalence of CYP2C19 polymorphisms involved in clopidogrel metabolism in Fujian Han population]
    Wei W, Fang L, Wang N, Zhang T, Zeng JB, Lin MT
    Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2012 Aug;29(4):420-5.
    PMID: 22875498 DOI: 10.3760/cma.j.issn.1003-9406.2012.04.009
    To investigate the frequency of CYP2C19 polymorphisms involved in clopidogrel metabolism in Fujian Han population.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  2. Fulltext Effects of brown rice and white rice on expression of xenobiotic metabolism genes in type 2 diabetic rats
    Imam MU, Ismail M
    Int J Mol Sci, 2012;13(7):8597-608.
    PMID: 22942722 DOI: 10.3390/ijms13078597
    Xenobiotics constantly influence biological systems through several means of interaction. These interactions are disturbed in type 2 diabetes, with implications for disease outcome. We aimed to study the implications of such disturbances on type 2 diabetes and rice consumption, the results of which could affect management of the disease in developing countries. In a type 2 diabetic rat model induced through a combination of high fat diet and low dose streptozotocin injection, up-regulation of xenobiotic metabolism genes in the diabetic untreated group was observed. Xenobiotic metabolism genes were upregulated more in the white rice (WR) group than the diabetic untreated group while the brown rice (BR) group showed significantly lower expression values, though not as effective as metformin, which gave values closer to the normal non-diabetic group. The fold changes in expression in the WR group compared to the BR group for Cyp2D4, Cyp3A1, Cyp4A1, Cyp2B1, Cyp2E1, Cyp2C11, UGT2B1, ALDH1A1 and Cyp2C6 were 2.6, 2, 1.5, 4, 2.8, 1.5, 1.8, 3 and 5, respectively. Our results suggest that WR may upregulate these genes in type 2 diabetes more than BR, potentially causing faster drug metabolism, less drug efficacy and more toxicity. These results may have profound implications for rice eating populations, constituting half the world's population.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics
  3. Malaysian Indians are genetically similar to Caucasians: CYP2C9 polymorphism
    Zainuddin Z, Teh LK, Suhaimi AW, Ismail R
    J Clin Pharm Ther, 2006 Apr;31(2):187-91.
    PMID: 16635054
    CYP2C9 is one of the major drug metabolizing enzymes for many drugs including warfarin, NSAIDs and losartan. It is polymorphic in many populations. Data on the distribution of CYP2C9 and the implication of CYP2C9 polymorphism in the Malaysian population is lacking. Our objectives were therefore to investigate the prevalence of CYP2C9 variants among unrelated healthy volunteers of Malays, Chinese and Indians in Malaysia.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  4. Genetic polymorphism of CYP2C8 in three Malaysian ethnics: CYP2C8*2 and CYP2C8*3 are found in Malaysian Indians
    Muthiah YD, Lee WL, Teh LK, Ong CE, Ismail R
    J Clin Pharm Ther, 2005 Oct;30(5):487-90.
    PMID: 16164496
    CYP2C8 is genetically polymorphic. Four variants, CYP2C8*2, CYP2C8*3, CYP2C8*4 and CYP2C8*5, which contain mutations in the coding regions have been reported to exhibit different enzyme activity as compared with CYP2C8*1.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  5. A simple method for the detection of CYP2C9 polymorphisms: nested allele-specific multiplex polymerase chain reaction
    Zainuddin Z, Teh LK, Suhaimi AW, Salleh MZ, Ismail R
    Clin Chim Acta, 2003 Oct;336(1-2):97-102.
    PMID: 14500040 DOI: 10.1016/s0009-8981(03)00319-x
    BACKGROUND: Cytochrome P4502C9 (CYP2C9), a principle drug-metabolizing enzyme is polymorphic in humans and is responsible for important pharmacokinetic and pharmacodynamic variations of CYP2C9 substrates. We developed an allele-specific multiplex polymerase chain reaction (PCR) method for the detection of common CYP2C9 alleles.
    METHOD: Genomic DNA was extracted from blood obtained from 40 unrelated healthy Malaysian Indian volunteers. The DNA was subjected to a first PCR that was used to amplify both exons 3 and 7 simultaneously in one reaction tube and a second PCR that was used to detect the polymorphic sites of CYP2C9 alleles using allele-specific primers. Sequencing was performed to validate the test results.
    RESULTS: We were successful in amplifying the fragments of interest from the DNA samples. The method was also reproducible and specific. The amplified sequences showed 100% homology to CYP2C9 sequence.
    CONCLUSION: This is the first nested allele-specific multiplex PCR method reported to allow for the simultaneously detection of five CYP2C9 alleles.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  6. Fulltext CYP2C9 polymorphism: prevalence in healthy and warfarin-treated Malay and Chinese in Malaysia
    Ngow HA, Wan Khairina WM, Teh LK, Lee WL, Harun R, Ismail R, et al.
    Singapore Med J, 2009 May;50(5):490-3.
    PMID: 19495518
    Genetic polymorphisms of CYP2C9 among different populations in different geographical regions could be different. CYP2C9 has been reported to be the enzyme responsible for the metabolism of many drugs, including warfarin and other drugs with a narrow therapeutic index. Realising the importance of inter-individual differences in the genetic profile in determining the outcome of a drug therapy, this study was conducted to explore the types and frequencies of CYP2C9 alleles in healthy and warfarin-treated Malays and Chinese, the two major ethnic groups in Malaysia. We aimed to evaluate the prevalence of the types and frequencies of common CYP2C9 alleles (*1, *2, *3 and *4) among the healthy unrelated individuals and diseased patients prescribed with warfarin.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  7. Fulltext Inhibitory potency of 8-methoxypsoralen on cytochrome P450 2A6 (CYP2A6) allelic variants CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22: differential susceptibility due to different sequence locations of the mutations
    Tiong KH, Mohammed Yunus NA, Yiap BC, Tan EL, Ismail R, Ong CE
    PLoS One, 2014;9(1):e86230.
    PMID: 24475091 DOI: 10.1371/journal.pone.0086230
    Human cytochrome P450 2A6 (CYP2A6) is a highly polymorphic isoform of CYP2A subfamily. Our previous kinetic study on four CYP2A6 allelic variants (CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22) have unveiled the functional significance of sequence mutations in these variants on coumarin 7-hydroxylation activity. In the present study, we further explored the ability of a typical CYP2A6 inhibitor, 8-methoxypsoralen (8-MOP), in inhibition of these alleles and we hypothesized that translational mutations in these variants are likely to give impact on 8-MOP inhibitory potency. The CYP2A6 variant and the wild type proteins were subjected to 8-MOP inhibition to yield IC50 values. In general, a similar trend of change in the IC50 and Km values was noted among the four mutants towards coumarin oxidation. With the exception of CYP2A6 16, differences in IC50 values were highly significant which implied compromised interaction of the mutants with 8-MOP. Molecular models of CYP2A6 were subsequently constructed and ligand-docking experiments were performed to rationalize experimental data. Our docking study has shown that mutations have induced enlargement of the active site volume in all mutants with the exception of CYP2A6 16. Furthermore, loss of hydrogen bond between 8-MOP and active site residue Asn297 was evidenced in all mutants. Our data indicate that the structural changes elicited by the sequence mutations could affect 8-MOP binding to yield differential enzymatic activities in the mutant CYP2A6 proteins.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  8. In vitro modulatory effects of flavonoids on human cytochrome P450 2C8 (CYP2C8)
    Pang CY, Mak JW, Ismail R, Ong CE
    Naunyn Schmiedebergs Arch Pharmacol, 2012 May;385(5):495-502.
    PMID: 22307090 DOI: 10.1007/s00210-012-0731-5
    The inhibitory effects of five flavonoids with distinct chemical classes (flavones [luteolin], flavonols [quercetin and quercitrin], and flavanones [hesperetin and hespiridin]) on cDNA-expressed CYP2C8 were investigated. CYP2C8 was co-expressed with NADPH-cytochrome P450 reductase in Escherichia coli and used to characterise potency and mechanism of these flavonoids on the isoform. Tolbutamide 4-methylhydroxylase, a high-performance liquid chromatography-based assay, was selected as marker activity for CYP2C8. Our results indicated that the flavonoids inhibited CYP2C8 with different potency. The order of inhibitory activities was quercetin > luteolin > hesperetin > hesperidin > quercitrin. All of these compounds however exhibited mechanism-based inhibition. A number of structural factors were found to be important for inhibition; these include the molecular shape (volume to surface ratio), the number of hydroxyl groups as well as glycosylation of the hydroxyl group. Quercetin was the most potent inhibitor among the flavonoids examined in this study, and our data suggest that it should be examined for potential pharmacokinetic drug interactions pertaining to CYP2C8 substrates in vivo.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics
  9. Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention
    Hasan MS, Basri HB, Hin LP, Stanslas J
    Int J Neurosci, 2013 Mar;123(3):143-54.
    PMID: 23110469 DOI: 10.3109/00207454.2012.744308
    Ischemic heart disease and stroke are the two leading causes of death worldwide. Antiplatelet therapy plays the most significant role in the management of these cardiovascular and cerebrovascular occlusive events to prevent recurrent ischemic attack. Clopidogrel, an antiplatelet drug, is widely prescribed either alone or in combination with aspirin as dual antiplatelet therapy for the prevention of vascular occlusive events. The antiplatelet response to clopidogrel varies widely. Hyporesponders and nonresponders are likely to have adverse cardiovascular events during follow-up. Some drugs, such as proton pump inhibitors (omeprazole), calcium channel blockers, selective serotonin reuptake inhibitors (nefazadone), coumarin derivatives (phenprocoumon), benzodiazepines, sulfonylurea, erythromycin, and itraconazole, decrease the antiplatelet effect of clopidogrel when administered concomitantly. Decreased response to clopidogrel is common among Asians due to genetic polymorphisms associated with clopidogrel resistance, and it is nearly 70% in some of the Asian communities. It is necessary to study Asian populations, because there are a large number of Asians throughout the world due to increased migration. Current guidelines do not make genetic testing or platelet response testing mandatory prior to clopidogrel prescription. Therefore, it is important for clinicians treating Asian patients to keep in mind the interindividual variability in response to clopidogrel when prescribing the drug.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics
  10. Mutational analysis of CYP2C8 in hypertensive patients using denaturing high performance liquid chromatography
    Teh LK, Zahri MK, Zakaria ZA, Ismail R, Salleh MZ
    J Clin Pharm Ther, 2010 Dec;35(6):723-8.
    PMID: 21054465 DOI: 10.1111/j.1365-2710.2009.01146.x
    CYP2C8 is involved in the cytochrome P450 (CYP) epoxygenase pathway. Arachidonic acid metabolites such as epoxyeicosatrienenoic acids and hydroxyeicosatetrenoic acids, produced may have a role in hypertension. We aimed to develop a medium through-put method for screening samples of known and new mutations of CYP2C8 using denaturing high performance liquid chromatography (DHPLC).
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  11. Fulltext Functional characterization of cytochrome P450 2A6 allelic variants CYP2A6*15, CYP2A6*16, CYP2A6*21, and CYP2A6*22
    Tiong KH, Yiap BC, Tan EL, Ismail R, Ong CE
    Drug Metab. Dispos., 2010 May;38(5):745-51.
    PMID: 20139165 DOI: 10.1124/dmd.109.031054
    Variation in CYP2A6 levels and activity can be attributed to genetic polymorphism and, thus, functional characterization of allelic variants is necessary to define the importance of CYP2A6 polymorphism in humans. The aim of the present study was to investigate the reported alleles CYP2A6*15, CYP2A6*16, CYP2A6*21, and CYP2A6*22, in terms of the functional consequences of their mutations on the enzyme catalytic activity. With use of the wild-type CYP2A6 cDNA as template, site-directed mutagenesis was performed to introduce nucleotide changes encoding K194E substitution in CYP2A6*15, R203S substitution in CYP2A6*16, K476R substitution in CYP2A6*21, and concurrent D158E and L160I substitutions in CYP2A6*22. Upon sequence verification, the CYP2A6 wild-type and mutant constructs were individually coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. A kinetic study using a coumarin 7-hydroxylase assay indicated that CYP2A6*15 exhibited higher V(max) than the wild type, whereas all mutant constructs, except for variant CYP2A6*16, exhibited higher K(m) values. Analysis of the V(max)/K(m) ratio revealed that all mutants demonstrated 0.85- to 1.05-fold differences from the wild type, with the exception of variant CYP2A6*22, which only portrayed 39% of the wild-type intrinsic clearance. These data suggested that individuals carrying the CYP2A6*22 allele are likely to have lower metabolism of CYP2A6 substrate than individuals expressing CYP2A6*15, CYP2A6*16, CYP2A6*21, and the wild type.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  12. Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects
    Pang YS, Yang YS, Wong LP, Lee TC, Mustafa AM, Mohamed Z, et al.
    Br J Clin Pharmacol, 2004 Sep;58(3):332-5.
    PMID: 15327595
    Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. Although ethnic differences in its distribution of polymorphism has been described, it is not known whether there is an ethnic heterogeneity of the structure and expression of the CYP2C19 enzyme in the Malaysian population.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  13. A simple multiplex PCR method for the concurrent detection of three CYP2C8 variants
    Muthiah YD, Lee WL, Teh LK, Ong CE, Salleh MZ, Ismail R
    Clin Chim Acta, 2004 Nov;349(1-2):191-8.
    PMID: 15469873 DOI: 10.1016/j.cccn.2004.06.024
    BACKGROUND: Cytochrome P450 (CYP) 2C8 is a principle enzyme responsible for the metabolism of many clinically important drugs as well as endogenous compounds such as arachidonic acid. The enzyme is genetically polymorphic but a simple method is not available to study its genetic polymorphism. We developed and optimized a variant-specific PCR techniques to detect CYP2C8*2, CYP2C8*3 and CYP2C8*4.
    METHOD: Genomic DNA was extracted from blood using standard extraction methods. A two-step PCR method was developed to detect simultaneously three CYP2C8 variants. In the first PCR (PCR1), specific regions from exons 3, 5 and 8 of the CYP2C8 gene were amplified. The products were used as templates in parallel alleles-specific PCR (PCR2). This method was tested against DNA samples obtained from 57 healthy Malaysian volunteers.
    RESULT: The bands of interest were successfully amplified. This method showed specific and reproducible results when tested on healthy volunteers. DNA sequencing further confirmed genotype results obtained from current method.
    CONCLUSION: We have successfully developed and optimized a multiplex PCR method suitable for use in population studies of CYP2C8 polymorphism.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  14. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions
    Chung WH, Chang WC, Lee YS, Wu YY, Yang CH, Ho HC, et al.
    JAMA, 2014 Aug 6;312(5):525-34.
    PMID: 25096692 DOI: 10.1001/jama.2014.7859
    The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  15. Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin
    Teh LK, Langmia IM, Fazleen Haslinda MH, Ngow HA, Roziah MJ, Harun R, et al.
    J Clin Pharm Ther, 2012 Apr;37(2):232-6.
    PMID: 21507031 DOI: 10.1111/j.1365-2710.2011.01262.x
    Testing for cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  16. Gene, ethnic and gender influences predisposition of adverse drug reactions to artesunate among Malaysians
    Yusof W, Hua GS
    Toxicol. Mech. Methods, 2012 Apr;22(3):184-92.
    PMID: 22003869 DOI: 10.3109/15376516.2011.623331
    Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  17. Genomic copy number variations in three Southeast Asian populations
    Ku CS, Pawitan Y, Sim X, Ong RT, Seielstad M, Lee EJ, et al.
    Hum Mutat, 2010 Jul;31(7):851-7.
    PMID: 20506136 DOI: 10.1002/humu.21287
    Research on the role of copy number variations (CNVs) in the genetic risk of diseases in Asian populations has been hampered by a relative lack of reference CNV maps for Asian populations outside the East Asians. In this article, we report the population characteristics of CNVs in Chinese, Malay, and Asian Indian populations in Singapore. Using the Illumina Human 1M Beadchip array, we identify 1,174 CNV loci in these populations that corroborated with findings when the same samples were typed on the Affymetrix 6.0 platform. We identify 441 novel loci not previously reported in the Database of Genomic Variations (DGV). We observe a considerable number of loci that span all three populations and were previously unreported, as well as population-specific loci that are quite common in the respective populations. From this we observe the distribution of CNVs in the Asian Indian population to be considerably different from the Chinese and Malay populations. About half of the deletion loci and three-quarters of duplication loci overlap UCSC genes. Tens of loci show population differentiation and overlap with genes previously known to be associated with genetic risk of diseases. One of these loci is the CYP2A6 deletion, previously linked to reduced susceptibility to lung cancer.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics
  18. Translational aspects of genetic factors in the prediction of drug response variability: a case study of warfarin pharmacogenomics in a multi-ethnic cohort from Asia
    Chan SL, Suo C, Lee SC, Goh BC, Chia KS, Teo YY
    Pharmacogenomics J, 2012 Aug;12(4):312-8.
    PMID: 21383771 DOI: 10.1038/tpj.2011.7
    Genetic markers displaying highly significant statistical associations with complex phenotypes may not necessarily possess sufficient clinical validity to be useful. Understanding the contribution of these markers beyond readily available clinical biomarkers is particularly important in pharmacogenetics. We demonstrate the utility of genetic testing using the example of warfarin in a multi-ethnic setting comprising of three Asian populations that are broadly representative of the genetic diversity for half of the population in the world, especially as distinct interethnic differences in warfarin dose requirements have been previously established. We confirmed the roles of three well-established loci (CYP2C9, VKORC1 and CYP4F2) in explaining warfarin dosage variation in the three Asian populations. In addition, we assessed the relationship between ethnicity and the genotypes of these loci, observing strong correlations at VKORC1 and CYP4F2. Subsequently, we established the additional utility of these genetic factors in predicting warfarin dose beyond ethnicity and clinical biomarkers through performing a series of systematic cross-validation analyses of the relative predictive accuracies of various fixed-dose regimen, clinical and genetic models. Through a pharmacogenetics model for warfarin, we show the importance of genetic testing beyond readily available clinical biomarkers in predicting dose requirements, confirming the role of genetic profiling in personalized medicine.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics
  19. CYP3A4 genetic polymorphism influences repaglinide's pharmacokinetics
    Ruzilawati AB, Gan SH
    Pharmacology, 2010;85(6):357-64.
    PMID: 20523106 DOI: 10.1159/000302731
    AIM: To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide's pharmacokinetics in healthy Malaysian subjects.

    METHODS: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles.

    RESULTS: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide's blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide's pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide.

    CONCLUSION: Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide's pharmacokinetics.

    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
  20. Functional role of Ile264 in CYP2C8: mutations affect haem incorporation and catalytic activity
    Singh R, Ting JG, Pan Y, Teh LK, Ismail R, Ong CE
    Drug Metab. Pharmacokinet., 2008;23(3):165-74.
    PMID: 18574320
    The work described in this study aimed to express CYP2C8 wild-type and mutant proteins in bacterial expression system and to use the expressed proteins to investigate the structural and functional consequences of a reported allele CYP2C8(*)4 (carrying Ile264Met substitution) on protein activity. Ile264 was replaced by three different amino acids resulting in three mutant constructs, 2C8I264M, 2C8I264R and 2C8I264D. The presence of isoleucine at position 264 in CYP2C8 was found to be important for proper haem insertion and protein folding; whereas bulkier or charged residues were highly disruptive resulting in inactive proteins with minimum spectral and catalytic activities. This was evidenced from the low levels of Soret peak at 450 nm and negligible levels of tolbutamide methylhydroxylase activity. Kinetic study using paclitaxel indicated that all three mutants exhibited only 9.7 to 35.4% of the activity level observed in the wild-type. In addition, the mutants were more sensitive to proteinase K digestion, indicating a possible alteration of conformation. The combined effects of protein instability and compromised catalytic activity resulted in defective CYP2C8 protein which may have clinical implications in carriers of CYP2C8*4, particularly in terms of their capacity to clear potent drugs and their susceptibility to adverse drug reactions.
    Matched MeSH terms: Aryl Hydrocarbon Hydroxylases/genetics*
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