Displaying publications 21 - 40 of 65 in total

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  1. Genetic polymorphisms of CYP3A4: CYP3A4*18 allele is found in five healthy Malaysian subjects
    Ruzilawati AB, Suhaimi AW, Gan SH
    Clin Chim Acta, 2007 Aug;383(1-2):158-62.
    PMID: 17601520 DOI: 10.1016/j.cca.2007.05.004
    BACKGROUND: Cytochrome P450 3A4 (CYP3A4) is the major cytochrome involved in metabolizing of >60% of all drugs used in humans. A number of allelic variations in CYP3A4 gene are known to affect catalytic activity including CYP3A4*4, CYP3A4*5 and CYP3A4*18. We investigated the frequencies of CYP3A4*4, CYP3A4*5 and CYP3A4*18 alleles in a Malaysian population. This will impact treatment of patients receiving drugs metabolized by these alleles.

    METHODS: The study was conducted in 121 healthy Malaysian volunteers. DNA was extracted from leucocytes and the 3 alleles were determined by PCR-RFLP. The PCR product was later digested with restriction enzymes BstMA I, BshV I and Hpa II.

    RESULTS: No mutations were detected for CYP3A4*4 and CYP3A4*5 alleles. The frequency of the CYP3A4*18 allele in the Malaysian population is 2.1%. All 5 subjects with CYP3A4*18 mutations were found to be heterozygous.

    CONCLUSION: The present study describes polymorphisms of CYP3A4 among Malaysian subjects. Clinical relevance of these genetic variants in these healthy volunteers is under investigation.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*
  2. Fulltext Role of Cytochrome P450 2C9 in COVID-19 Treatment: Current Status and Future Directions
    Lim SYM, Al Bishtawi B, Lim W
    Eur J Drug Metab Pharmacokinet, 2023 May;48(3):221-240.
    PMID: 37093458 DOI: 10.1007/s13318-023-00826-8
    The major human liver drug metabolising cytochrome P450 (CYP) enzymes are downregulated during inflammation and infectious disease state, especially during coronavirus disease 2019 (COVID-19) infection. The influx of proinflammatory cytokines, known as a 'cytokine storm', during severe COVID-19 leads to the downregulation of CYPs and triggers new cytokine release, which further dampens CYP expression. Impaired drug metabolism, along with the inevitable co-administration of drugs or 'combination therapy' in patients with COVID-19 with various comorbidities, could cause drug-drug interactions, thus worsening the disease condition. Genetic variability or polymorphism in CYP2C9 across different ethnicities could contribute to COVID-19 susceptibility. A number of drugs used in patients with COVID-19 are inducers or inhibitors of, or are metabolised by, CYP2C9, and co-administration might cause pharmacokinetic and pharmacodynamic interactions. It is also worth mentioning that some of the COVID-19 drug interactions are due to altered activity of other CYPs including CYP3A4. Isoniazid/rifampin for COVID-19 and tuberculosis co-infection; lopinavir/ritonavir and cobicistat/remdesivir combination therapy; or multi-drug therapy including ivermectin, azithromycin, montelukast and acetylsalicylic acid, known as TNR4 therapy, all improved recovery in patients with COVID-19. However, a combination of CYP2C9 inducers, inhibitors or both, and plausibly different CYP isoforms could lead to treatment failure, hepatotoxicity or serious side effects including thromboembolism or bleeding, as observed in the combined use of azithromycin/warfarin. Further, herbs that are CYP2C9 inducers and inhibitors, showed anti-COVID-19 properties, and in silico predictions postulated that phytochemical compounds could inhibit SARS-CoV-2 virus particles. COVID-19 vaccines elicit immune responses that activate cytokine release, which in turn suppresses CYP expression that could be the source of compromised CYP2C9 drug metabolism and the subsequent drug-drug interaction. Future studies are recommended to determine CYP regulation in COVID-19, while recognising the involvement of CYP2C9 and possibly utilising CYP2C9 as a target gene to tackle the ever-mutating SARS-CoV-2.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism
  3. Fulltext Exosomes drive ferroptosis by stimulating iron accumulation to inhibit bacterial infection in crustaceans
    Sun Q, Yang J, Zhang M, Zhang Y, Ma H, Tran NT, et al.
    J Biol Chem, 2023 Dec;299(12):105463.
    PMID: 37977221 DOI: 10.1016/j.jbc.2023.105463
    Ferroptosis, characterized by iron-dependent cell death, has recently emerged as a critical defense mechanism against microbial infections. The present study aims to investigate the involvement of exosomes in the induction of ferroptosis and the inhibition of bacterial infection in crustaceans. Our findings provide compelling evidence for the pivotal role of exosomes in the immune response of crustaceans, wherein they facilitate intracellular iron accumulation and activate the ferroptotic pathways. Using RNA-seq and bioinformatic analysis, we demonstrate that cytochrome P450 (CYP) can effectively trigger ferroptosis. Moreover, by conducting an analysis of exosome cargo proteins, we have identified the participation of six-transmembrane epithelial antigen of prostate 4 in the regulation of hemocyte ferroptotic sensitivity. Subsequent functional investigations unveil that six-transmembrane epithelial antigen of prostate 4 enhances cellular Fe2+ levels, thereby triggering Fenton reactions and accelerating CYP-mediated lipid peroxidation, ultimately culminating in ferroptotic cell death. Additionally, the Fe2+-dependent CYP catalyzes the conversion of arachidonic acid into 20-hydroxyeicosatetraenoic acid, which activates the peroxisome proliferator-activated receptor. Consequently, the downstream target of peroxisome proliferator-activated receptor, cluster of differentiation 36, promotes intracellular fatty acid accumulation, lipid peroxidation, and ferroptosis. These significant findings shed light on the immune defense mechanisms employed by crustaceans and provide potential strategies for combating bacterial infections in this species.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism
  4. Fulltext Role of genetic & environment risk factors in the aetiology of colorectal cancer in Malaysia
    Ramzi NH, Chahil JK, Lye SH, Munretnam K, Sahadevappa KI, Velapasamy S, et al.
    Indian J Med Res, 2014 Jun;139(6):873-82.
    PMID: 25109722
    Colorectal cancer (CRC) is second only to breast cancer as the leading cause of cancer-related deaths in Malaysia. In the Asia-Pacific area, it is the highest emerging gastrointestinal cancer. The aim of this study was to identify single nucleotide polymorphisms (SNPs) and environmental factors associated with CRC risk in Malaysia from a panel of cancer associated SNPs.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*
  5. Fulltext Computational identification and binding analysis of orphan human cytochrome P450 4X1 enzyme with substrates
    Kumar S
    BMC Res Notes, 2015;8:9.
    PMID: 25595103 DOI: 10.1186/s13104-015-0976-4
    Cytochrome P450s (CYPs) are important heme-containing proteins, well known for their monooxygenase reaction. The human cytochrome P450 4X1 (CYP4X1) is categorized as "orphan" CYP because of its unknown function. In recent studies it is found that this enzyme is expressed in neurovascular functions of the brain. Also, various studies have found the expression and activity of orphan human cytochrome P450 4X1 in cancer. It is found to be a potential drug target for cancer therapy. However, three-dimensional structure, the active site topology and substrate specificity of CYP4X1 remain unclear.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism*; Cytochrome P-450 Enzyme System/chemistry*
  6. Andrographolide and 14-deoxy-11, 12-didehydroandrographolide inhibit cytochrome P450s in HepG2 hepatoma cells
    Ooi JP, Kuroyanagi M, Sulaiman SF, Muhammad TS, Tan ML
    Life Sci, 2011 Feb 28;88(9-10):447-54.
    PMID: 21219911 DOI: 10.1016/j.lfs.2010.12.019
    Cytochrome P450 (CYP) enzymes have been implicated in a large number of preventable drug-herb interactions. Andrographis paniculata Nees, a tropical herb widely used for various health conditions contains two major diterpenoids, andrographolide and 14-Deoxy-11, 12-Didehydroandrographolide. These compounds were evaluated systematically for their effects on CYP1A2, CYP2D6 and CYP3A4 expressions in HepG2 cells.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics; Cytochrome P-450 Enzyme System/metabolism
  7. Frequency of mutant CYP1A1, NAT2 and GSTM1 alleles in normal Indians and Malays
    Zhao B, Lee EJ, Wong JY, Yeoh PN, Gong NH
    Pharmacogenetics, 1995 Oct;5(5):275-80.
    PMID: 8563767
    Several xenobiotic metabolizing enzymes, including CYP1A1, NAT2 and GSTM1, are subject to genetic polymorphisms. Because these enzymes are important for the detoxification and/or bioactivation of drugs and carcinogens, these polymorphisms have important implications in therapeutics and cancer susceptibility. The distributions of CYP1A1, NAT2 and GSTM1 genotype frequencies in unrelated individuals of the Indian (n = 139) and Malay (n = 146) populations were characterized by the polymerase chain reaction. The respective allelic frequencies of wild-type and mutant alleles of CYP1A1 were 0.82 and 0.18 for the Indians, and 0.69 and 0.31 for the Malays. The frequencies of wild-type, M1, M2 and M3 of NAT2 among Indians were 0.44, 0.20, 0.32 and 0.04 respectively. The corresponding NAT2 allelic frequencies in Malays were 0.41, 0.12, 0.38 and 0.09. The GSTM1*A allele could not be amplified in 33.1% of Indians and 61.6% of Malays. At least one GSTM1*B allele was detected in 7.2% and 7.5% of the respective populations. The allelic frequencies of CYP1A1, NAT2 and GSTM1 among Malays are similar to previously reported frequencies among Chinese in the region. These findings will be of importance in the determination of cancer risks in these populations.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*; Cytochrome P-450 Enzyme System/metabolism
  8. Fulltext Pyrethroid Resistance in Malaysian Populations of Dengue Vector Aedes aegypti Is Mediated by CYP9 Family of Cytochrome P450 Genes
    Ishak IH, Kamgang B, Ibrahim SS, Riveron JM, Irving H, Wondji CS
    PLoS Negl Trop Dis, 2017 01;11(1):e0005302.
    PMID: 28114328 DOI: 10.1371/journal.pntd.0005302
    BACKGROUND: Dengue control and prevention rely heavily on insecticide-based interventions. However, insecticide resistance in the dengue vector Aedes aegypti, threatens the continued effectiveness of these tools. The molecular basis of the resistance remains uncharacterised in many endemic countries including Malaysia, preventing the design of evidence-based resistance management. Here, we investigated the underlying molecular basis of multiple insecticide resistance in Ae. aegypti populations across Malaysia detecting the major genes driving the metabolic resistance.

    METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide microarray-based transcription analysis was carried out to detect the genes associated with metabolic resistance in these populations. Comparisons of the susceptible New Orleans strain to three non-exposed multiple insecticide resistant field strains; Penang, Kuala Lumpur and Kota Bharu detected 2605, 1480 and 425 differentially expressed transcripts respectively (fold-change>2 and p-value ≤ 0.05). 204 genes were commonly over-expressed with monooxygenase P450 genes (CYP9J27, CYP6CB1, CYP9J26 and CYP9M4) consistently the most up-regulated detoxification genes in all populations, indicating that they possibly play an important role in the resistance. In addition, glutathione S-transferases, carboxylesterases and other gene families commonly associated with insecticide resistance were also over-expressed. Gene Ontology (GO) enrichment analysis indicated an over-representation of GO terms linked to resistance such as monooxygenases, carboxylesterases, glutathione S-transferases and heme-binding. Polymorphism analysis of CYP9J27 sequences revealed a high level of polymorphism (except in Joho Bharu), suggesting a limited directional selection on this gene. In silico analysis of CYP9J27 activity through modelling and docking simulations suggested that this gene is involved in the multiple resistance in Malaysian populations as it is predicted to metabolise pyrethroids, DDT and bendiocarb.

    CONCLUSION/SIGNIFICANCE: The predominant over-expression of cytochrome P450s suggests that synergist-based (PBO) control tools could be utilised to improve control of this major dengue vector across Malaysia.

    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics; Cytochrome P-450 Enzyme System/metabolism*
  9. In vitro inhibitory mechanisms and molecular docking of 1'-S-1'-acetoxychavicol acetate on human cytochrome P450 enzymes
    Haque AKMM, Leong KH, Lo YL, Awang K, Nagoor NH
    Phytomedicine, 2017 Jul 15;31:1-9.
    PMID: 28606510 DOI: 10.1016/j.phymed.2017.05.002
    BACKGROUND: The compound, 1'-S-1'-acetoxychavicol acetate (ACA), isolated from the rhizomes of a Malaysian ethno-medicinal plant, Alpinia conchigera Griff. (Zingiberaceae), was previously shown to have potential in vivo antitumour activities. In the development of a new drug entity, potential interactions of the compound with the cytochrome P450 superfamily metabolizing enzymes need to be ascertain.

    PURPOSE: The concomitant use of therapeutic drugs may cause potential drug-drug interactions by decreasing or increasing plasma levels of the administered drugs, leading to a suboptimal clinical efficacy or a higher risk of toxicity. Thus, evaluating the inhibitory potential of a new chemical entity, and to clarify the mechanism of inhibition and kinetics in the various CYP enzymes is an important step to predict drug-drug interactions.

    STUDY DESIGN: This study was designed to assess the potential inhibitory effects of Alpinia conchigera Griff. rhizomes extract and its active constituent, ACA, on nine c-DNA expressed human cytochrome P450s (CYPs) enzymes using fluorescent CYP inhibition assay.

    METHODS/RESULTS: The half maximal inhibitory concentration (IC50) of Alpinia conchigera Griff. rhizomes extract and ACA was determined for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. A. conchigera extract only moderately inhibits on CYP3A4 (IC50 = 6.76 ± 1.88µg/ml) whereas ACA moderately inhibits the activities of CYP1A2 (IC50 = 4.50 ± 0.10µM), CYP2D6 (IC50 = 7.50 ± 0.17µM) and CYP3A4 (IC50 = 9.50 ± 0.57µM) while other isoenzymes are weakly inhibited. In addition, mechanism-based inhibition studies reveal that CYP1A2 and CYP3A4 exhibited non-mechanism based inhibition whereas CYP2D6 showed mechanism-based inhibition. Lineweaver-Burk plots depict that ACA competitively inhibited both CYP1A2 and CYP3A4, with a Ki values of 2.36 ± 0.03 µM and 5.55 ± 0.06µM, respectively, and mixed inhibition towards CYP2D6 with a Ki value of 4.50 ± 0.08µM. Further, molecular docking studies show that ACA is bound to a few key amino acid residues in the active sites of CYP1A2 and CYP3A4, while one amino residue of CYP2D6 through predominantly Pi-Pi interactions.

    CONCLUSION: Overall, ACA may demonstrate drug-drug interactions when co-administered with other therapeutic drugs that are metabolized by CYP1A2, CYP2D6 or CYP3A4 enzymes. Further in vivo studies, however, are needed to evaluate the clinical significance of these interactions.

    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics; Cytochrome P-450 Enzyme System/metabolism
  10. Fulltext In silico identification of novel tuberculosis drug targets in mycobacterium tuberculosis P450 enzymes by interaction study with azole drugs
    Suresh Kumar
    Malaysian Journal of Medicine and Health Sciences, 2020;16(101):24-30.
    MyJurnal
    Introduction: Tuberculosis (TB) is one of the utmost serious infectious diseases worldwide. The emergence of multi- drug resistance demands the development of better or new putative drug targets for tuberculosis. Recent studies sug- gest Mycobacterium tuberculosis cytochrome P450 enzymes as promising drug targets and azole drugs as potential inhibitors. Methods: Various computational tools, like Expasy Protparam, Swiss model, RaptorX and Phyre2 were used to analyze 12 Mycobacterium tuberculosis P450 enzymes and determine their three-dimensional structure. The structural validation was done through a Ramachandran plot using RAMPAGE server. The docking of P450 enzymes with azole drugs was done with autodock ver 4.2.6. Results: Based on sub-cellular localization prediction using CEL- LO tool, P450 enzymes CYP123A1, CYP132A1, CYP135A1, CYP136A1, CYP140A1, and CYP143A1 were predicted to be in the cytoplasm. Through structure assessment by Ramachandran plot, the best homology modelled proteins were docked with azole drugs like clotrimazole, croconazole, econazole, fluconazole, itraconazole, itraconazole, ketaconazole and micronazole by using autodock. By docking method it is identified that ketaconazole drug has a high affinity towards most of the mycobacterium P450 enzymes followed by the itrconazole drug. CYP123A1 enzyme is preferable as a drug target due to high binding affinity towards ketoconazole followed by CYP135A1, CYP140A1 enzymes. Conclusion: This study would help in identifying putative novel drug targets in Mycobacterium tuberculosis, which can lead to promising candidates for the optimization and development of novel anti-mycobac- terial agents.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  11. Arabidopsis at2g02870 loss of function mutants lead to enhanced production of hydroperoxide lyase pathway genes and products
    Muhammad Naeem-ul-Hassan, Zamri Zainal, Ismanizan Ismail, Nur Athirah Abd Hamid, Muhammad Sajad
    Sains Malaysiana, 2018;47:3003-3008.
    F-box proteins containing variable C-terminal domains make an essential part of SKP1-Cullin-Ring box-F box (SCF)
    complex. SCF complex catalyzes the final step to link the ubiquitin tag with the target protein, destined for degradation,
    through F-box protein that confer overall substrate specificity to the complex. In this study, we analyzed the role of
    At2g02870, a Kelch containing F-box protein from Arabidopsis thaliana, by using reverse genetics strategy. At2g02870
    loss of function mutant lines (at2g02870) were analyzed and compared with wild type plants for the expression of genes
    and products of hydroperoxide lyase (HPL) branch of oxylipin pathway. We found that the at2g02870 plants have enhanced
    expression of HPL pathway genes and produce more green leaf volatiles (GLV) than the wild type plants. Our results
    suggested that the gene is involved in the regulation of HPL pathway, possibly through the degradation of enzymes or/
    and the regulatory factors of the pathway.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  12. Fulltext Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data
    Ang GY, Yu CY, Subramaniam V, Abdul Khalid MI, Tuan Abdu Aziz TA, Johari James R, et al.
    PLoS One, 2016;11(10):e0164169.
    PMID: 27798644 DOI: 10.1371/journal.pone.0164169
    The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme's activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.
    Matched MeSH terms: Cytochrome P-450 Enzyme System
  13. Inhibitory effects of cytochrome P450 enzymes CYP2C8, CYP2C9, CYP2C19 and CYP3A4 by Labisia pumila extracts
    Pan Y, Tiong KH, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, et al.
    J Ethnopharmacol, 2012 Sep 28;143(2):586-91.
    PMID: 22885070 DOI: 10.1016/j.jep.2012.07.024
    Labisa pumila (LP), popularly known with its local name, Kacip Fatimah, is a well known herb grown in Indochina and Southeast Asia and is traditionally used to regain energy after giving birth in women. The propensity of LP to cause drug-herb interaction via cytochrome P450 (CYP) enzyme system has not been investigated.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/metabolism
  14. 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: Cytochrome P-450 Enzyme System/metabolism
  15. Fulltext The chromosome-scale reference genome of black pepper provides insight into piperine biosynthesis
    Hu L, Xu Z, Wang M, Fan R, Yuan D, Wu B, et al.
    Nat Commun, 2019 10 16;10(1):4702.
    PMID: 31619678 DOI: 10.1038/s41467-019-12607-6
    Black pepper (Piper nigrum), dubbed the 'King of Spices' and 'Black Gold', is one of the most widely used spices. Here, we present its reference genome assembly by integrating PacBio, 10x Chromium, BioNano DLS optical mapping, and Hi-C mapping technologies. The 761.2 Mb sequences (45 scaffolds with an N50 of 29.8 Mb) are assembled into 26 pseudochromosomes. A phylogenomic analysis of representative plant genomes places magnoliids as sister to the monocots-eudicots clade and indicates that black pepper has diverged from the shared Laurales-Magnoliales lineage approximately 180 million years ago. Comparative genomic analyses reveal specific gene expansions in the glycosyltransferase, cytochrome P450, shikimate hydroxycinnamoyl transferase, lysine decarboxylase, and acyltransferase gene families. Comparative transcriptomic analyses disclose berry-specific upregulated expression in representative genes in each of these gene families. These data provide an evolutionary perspective and shed light on the metabolic processes relevant to the molecular basis of species-specific piperine biosynthesis.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics
  16. Fulltext Analysis of Genetic Variation in CYP450 Genes for Clinical Implementation
    Goh LL, Lim CW, Sim WC, Toh LX, Leong KP
    PLoS One, 2017;12(1):e0169233.
    PMID: 28046094 DOI: 10.1371/journal.pone.0169233
    BACKGROUND: Genetic determinants of drug response remain stable throughout life and offer great promise to patient-tailored drug therapy. The adoption of pharmacogenetic (PGx) testing in patient care requires accurate, cost effective and rapid genotyping with clear guidance on the use of the results. Hence, we evaluated a 32 SNPs panel for implementing PGx testing in clinical laboratories.

    METHODS: We designed a 32-SNP panel for PGx testing in clinical laboratories. The variants were selected using the clinical annotations of the Pharmacogenomics Knowledgebase (PharmGKB) and include polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A5 and VKORC1 genes. The CYP2D6 gene allele quantification was determined simultaneously with TaqMan copy number assays targeting intron 2 and exon 9 regions. The genotyping results showed high call rate accuracy according to concordance with genotypes identified by independent analyses on Sequenome massarray and droplet digital PCR. Furthermore, 506 genomic samples across three major ethnic groups of Singapore (Malay, Indian and Chinese) were analysed on our workflow.

    RESULTS: We found that 98% of our study subjects carry one or more CPIC actionable variants. The major alleles detected include CYP2C9*3, CYP2C19*2, CYP2D6*10, CYP2D6*36, CYP2D6*41, CYP3A5*3 and VKORC1*2. These translate into a high percentage of intermediate (IM) and poor metabolizer (PM) phenotypes for these genes in our population.

    CONCLUSION: Genotyping may be useful to identify patients who are prone to drug toxicity with standard doses of drug therapy in our population. The simplicity and robustness of this PGx panel is highly suitable for use in a clinical laboratory.

    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics*
  17. Fulltext Genome sequence of the alkane-degrading bacterium Alcanivorax hongdengensis type strain A-11-3
    Lai Q, Shao Z
    J Bacteriol, 2012 Dec;194(24):6972.
    PMID: 23209226 DOI: 10.1128/JB.01849-12
    Alcanivorax hongdengensis A-11-3(T) was isolated from an oil-enriched consortium enriched from the surface seawater of Hong-Deng dock in the Straits of Malacca and Singapore. Strain A-11-3(T) can degrade n-alkane and produce a lipopeptide biosurfactant. Here we report the genome of A-11-3(T) and the genes associated with alkane degradation.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/genetics
  18. The effects of Andrographis paniculata (Burm.f.) Nees extract and diterpenoids on the CYP450 isoforms' activities, a review of possible herb-drug interaction risks
    Tan ML, Lim LE
    Drug Chem Toxicol, 2015;38(3):241-53.
    PMID: 25156015 DOI: 10.3109/01480545.2014.947504
    Andrographis paniculata (Burm.f.) Nees is a popular medicinal plant and its components are used in various traditional product preparations. However, its herb-drug interactions risks remain unclear. This review specifically discusses the various published studies carried out to evaluate the effects of Andrographis paniculata (Burm.f.) Nees plant extracts and diterpenoids on the CYP450 metabolic enzyme and if the plant components pose a possible herb-drug interaction risk. Unfortunately, the current data are insufficient to indicate if the extracts or diterpenoids can be labeled as in vitro CYP1A2, CYP2C9 or CYP3A4 inhibitors. A complete CYP inhibition assay utilizing human liver microsomes and the derivation of relevant parameters to predict herb-drug interaction risks may be necessary for these isoforms. However, based on the current studies, none of the extracts and diterpenoids exhibited CYP450 induction activity in human hepatocytes or human-derived cell lines. It is crucial that a well-defined experimental design is needed to make a meaningful herb-drug interaction prediction.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/biosynthesis; Cytochrome P-450 Enzyme System/metabolism*
  19. Fulltext CYP2S1 and CYP2W1 mediate 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610, NSC 721648) sensitivity in breast and colorectal cancer cells
    Tan BS, Tiong KH, Muruhadas A, Randhawa N, Choo HL, Bradshaw TD, et al.
    Mol. Cancer Ther., 2011 Oct;10(10):1982-92.
    PMID: 21831963 DOI: 10.1158/1535-7163.MCT-11-0391
    Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F-203; NSC 703786) and 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (GW-610; NSC 721648) are antitumor agents with novel mechanism(s). Previous studies have indicated that cytochrome (CYP) P450 1A1 is crucial for 5F-203 activity. In the present study, we investigated the functional role of 2 newly identified CYP P450 enzymes, CYP2S1 and CYP2W1, in mediating antitumor activity of benzothiazole compounds. We generated isogenic breast cancer (MDA-MB-468, MCF-7) and colorectal cancer (CRC; KM12 and HCC2998) cell lines depleted for CYP1A1, CYP2S1, or CYP2W1. The sensitivity of these cells to 5F-203 and GW-610 was then compared with vector control cells. 5F-203 exhibited potent activity against breast cancer cells, whereas GW-610 was effective against both breast and colorectal cancer cells. CYP1A1 was induced in both breast cancer and CRC cells, while CYP2S1 and CYP2W1 were selectively induced in breast cancer cells only following treatment with 5F-203 or GW-610. Depletion of CYP1A1 abrogated the sensitivity of breast cancer and CRC cells to 5F-203 and GW-610. Although depletion of CYP2S1 sensitized both breast cancer and CRC cells toward 5F-203 and GW-610, CYP2W1 knockdown caused marked resistance to GW-610 in CRC cells. Our results indicate that CYP-P450 isoforms, with the exception of CYP1A1, play an important role in mediating benzothiazole activity. CYP2S1 appears to be involved in deactivation of benzothiazoles, whereas CYP2W1 is important for bioactivation of GW-610 in CRC cells. Because CYP2W1 is highly expressed in colorectal tumors, GW-610 represents a promising agent for CRC therapy.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/biosynthesis; Cytochrome P-450 Enzyme System/metabolism*
  20. Fulltext Ternary copper(II) complex: NCI60 screening, toxicity studies, and evaluation of efficacy in xenograft models of nasopharyngeal carcinoma
    Ahmad M, Suhaimi SN, Chu TL, Abdul Aziz N, Mohd Kornain NK, Samiulla DS, et al.
    PLoS One, 2018;13(1):e0191295.
    PMID: 29329342 DOI: 10.1371/journal.pone.0191295
    Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity.
    Matched MeSH terms: Cytochrome P-450 Enzyme System/biosynthesis; Cytochrome P-450 Enzyme System/metabolism
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