1.Genetic polymorphisms of CYP2D6 in Chinese mainland.
Ling JI ; Shixiu PAN ; Jianmin WU ; Jacqueline MARTI-JAUN ; Martin HERSBERGER
Chinese Medical Journal 2002;115(12):1780-1784
<p>OBJECTIVETo observe the significant differences in the frequencies of the cytochrome P450 2D6 (CYP2D6) alleles in Chinese popoulations.p><p>METHODSTetra-primer polymerase chain reaction (PCR), allele specific amplification (ASA) PCR and multiplex long PCR were developed to detect the CYP2D6 alleles * 2, * 3, * 4, * 5, * 6, * 8, * 10 and * 14 in 223 subjects from Chinese mainland.p><p>RESULTSThe CYP2D6 * 5 allele was the most frequent poor metabolizer (PM) allele in Chinese (7.2%), followed by CYP2D6 * 14 (2.0%) which was only detected in orientals. There was only 0.2% CYP2D6 * 4, and no CYP2D6 * 3, * 6 and * 8 were detected. In contrast to the Caucasians, the most frequent allele in Chinese was the * 10 allele with a frequency of 51.6%.p><p>CONCLUSIONThe frequencies of PM alleles, CYP2D6 * 5 and CYP2D6 * 14, were higher; but the frequency of CYP2D6 * 10 was lower in mainland Chinese population than that in other orientals.p>
Alleles
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China
;
Cytochrome P-450 CYP2D6
;
genetics
;
Humans
;
Polymorphism, Genetic
2.The prevalence of CYP2D6 Gene Polymorphisms among Filipinos and their use as biomarkers for lung cancer risk
Eva Maria Cutiongco-de la Paz ; Corazon A. Ngelangel ; Aileen David-Wang ; Jose B. Nevado Jr. ; Catherine Lynn T. Silao ; Rosalyn Hernandez-Sebastian ; Richmond B. Ceniza ; Leander Linus Philip P. Simpao ; Lakan U. Beratio ; Eleanor A. Dominguez ; Albert B. Albay Jr ; Rey A. Desales ; Nelia Tan-Liu ; Sullian Sy-Naval ; Roberto M. Montevirgen ; Catalina de Siena Gonda-Dimayacyac ; Pedrito Y. Tagayuna ; Elizabeth A. Nuqui ; Arnold Joseph M. Fernandez ; Andrew D. Dimacali ; Maria Constancia Obrerro-Carrillo ; Virgilio P. Banez ; Oliver G. Florendo G. Florendo ; Ma. Cecilia M. Sison ; Francisco T. Roxas ; Alberto B. Roxas ; Orlino C. Bisquera Jr. ; Luminardo M. Ramos ; John A. Coloma ; Higinio T. Mappala ; Alex C. Tapia ; Emmanuel F. Montana Jr. ; Jonathan M. Asprer ; Reynaldo O. Joson ; Sergio P. Paguio ; Conrado C. Cajucom ; Richard C. Tia ; Tristan Chipongian ; Joselito F. David ; Florentino C. Doble ; Maria Noemi G. Pato ; Hans Francis D. Ferraris ; Benito B. Bionat Jr. ; Adonis A. Guancia ; Eriberto R. Layda ; Frances Maureen C. Rocamora ; Roemel Jeusep Bueno ; Carmencita D. Padilla
Acta Medica Philippina 2017;51(3):207-215
Objectives:
The highly polymorphic nature of the CYP2D6 gene and its central role in the metabolism of commonly used drugs make it an ideal candidate for pharmacogenetic screening. This study aims to determine the prevalence of CYP2D6 polymorphisms among Filipinos and their association to lung cancer.
Method:
Forty seven single nucleotide polymorphisms (SNPs) of the CYP2D6 gene were genotyped from DNA samples of 115 cases with lung cancer and age- and sex-matched 115 controls.
Results:
Results show that 18 out of 47 polymorphisms have significant genotypic variability (>1% for at least 2 genotypes). No variant is associated with lung cancer. However, rs1135840,
rs16947 and rs28360521, were found to be highly variable among Filipinos.
Conclusion
This study demonstrated that CYP2D6 polymorphisms are present among Filipinos, which, although not found to be associated with lung cancer, can be useful biomarkers for future pharmacogenetic studies. The SNP rs16947 is found to be associated with cancer and timolol-induced bradycardia; the SNP rs1135840, on the other hand, is only shown to be linked with cancer. The genetic variant rs28360521 is known to be associated with low-dose aspirin-induced lower gastrointestinal bleeding.
Pharmacogenetics
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Cytochrome P-450 CYP2D6
;
Lung Neoplasms
;
Biomarkers
3.A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity.
Min SONG ; Hyunhee DO ; Oh Kwang KWON ; Eun Ju YANG ; Jong Sup BAE ; Tae Cheon JEONG ; Kyung Sik SONG ; Sangkyu LEE
Biomolecules & Therapeutics 2014;22(2):155-160
Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2-33.7 muM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.
Cytochrome P-450 CYP1A2
;
Cytochrome P-450 CYP2D6
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Cytochrome P-450 CYP2E1
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Cytochrome P-450 Enzyme System*
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Humans
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Hydrolysis
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Metabolism
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Microsomes, Liver
;
Proadifen*
;
Protein Isoforms
4.Investigation on the hydroxylation metabolism of imrecoxib in vitro by using recombinant human CYPs.
Qiang LI ; Hai-Hua HUANG ; Yu DONG ; Da-Fang ZHONG
Acta Pharmaceutica Sinica 2005;40(10):912-915
<p>AIMTo identify the drug-metabolizing enzymes involved in the hydroxylation of the new anti-inflammatory and anodyne imrecoxib.p><p>METHODSImrecoxib was incubated with heterologous expression human cytochrome P450 (rCYPs) in vitro, and metabolites and remained parent drug were detected with liquid chromatography-multistage mass spectrometry. The contribution of 4 CYPs in the hydroxylation metabolism of imrecoxib was evaluated by total normalized rate (TNR) method.p><p>RESULTSImrecoxib is metabolized by CYP2C9, CYP2D6 and CYP3A4, with the rate of 62.5%, 21.1% and 16.4%, respectively.p><p>CONCLUSIONCYP2C9 is the major enzyme involved in imrecoxib hydroxylation metabolism.p>
Aryl Hydrocarbon Hydroxylases
;
metabolism
;
Cyclooxygenase 2 Inhibitors
;
metabolism
;
Cytochrome P-450 CYP2C9
;
Cytochrome P-450 CYP2D6
;
metabolism
;
Cytochrome P-450 CYP3A
;
Cytochrome P-450 Enzyme System
;
metabolism
;
Hydroxylation
;
Pyrroles
;
metabolism
;
Spectrometry, Mass, Electrospray Ionization
;
Sulfides
;
metabolism
5.Prediction and visualization of CYP2D6 genotype-based phenotype using clustering algorithms.
Eun Young KIM ; Sang Goo SHIN ; Jae Gook SHIN
Translational and Clinical Pharmacology 2017;25(3):147-152
This study focused on the role of cytochrome P450 2D6 (CYP2D6) genotypes to predict phenotypes in the metabolism of dextromethorphan. CYP2D6 genotypes and metabolic ratios (MRs) of dextromethorphan were determined in 201 Koreans. Unsupervised clustering algorithms, hierarchical and k-means clustering analysis, and color visualizations of CYP2D6 activity were performed on a subset of 130 subjects. A total of 23 different genotypes were identified, five of which were observed in one subject. Phenotype classifications were based on the means, medians, and standard deviations of the log MR values for each genotype. Color visualization was used to display the mean and median of each genotype as different color intensities. Cutoff values were determined using receiver operating characteristic curves from the k-means analysis, and the data were validated in the remaining subset of 71 subjects. Using the two highest silhouette values, the selected numbers of clusters were three (the best) and four. The findings from the two clustering algorithms were similar to those of other studies, classifying *5/*5 as a lowest activity group and genotypes containing duplicated alleles (i.e., CYP2D6*1/*2N) as a highest activity group. The validation of the k-means clustering results with data from the 71 subjects revealed relatively high concordance rates: 92.8% and 73.9% in three and four clusters, respectively. Additionally, color visualization allowed for rapid interpretation of results. Although the clustering approach to predict CYP2D6 phenotype from CYP2D6 genotype is not fully complete, it provides general information about the genotype to phenotype relationship, including rare genotypes with only one subject.
Alleles
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Classification
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Cluster Analysis*
;
Cytochrome P-450 CYP2D6*
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Dextromethorphan
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Genotype
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Metabolism
;
Phenotype*
;
ROC Curve
6.Hiccup Due to Aripiprazole Plus Methylphenidate Treatment in an Adolescent with Attention Deficit and Hyperactivity Disorder and Conduct Disorder: A Case Report.
Meryem Ozlem KUTUK ; Gulen GULER ; Ali Evren TUFAN ; Ozgur KUTUK
Clinical Psychopharmacology and Neuroscience 2017;15(4):410-412
Our case had hiccups arising in an adolescent with the attention deficit and hyperactivity disorder (ADHD) and conduct disorder (CD) after adding aripiprazole treatment to extended-release methylphenidate. Actually, antipsychotics are also used in the treatment of hiccups, but studies suggest that they can cause hiccups as well. Within 12 hours of taking 2.5 mg aripiprazole added to extended-release methylphenidate at a dose of 54 mg/day, 16-year-old boy began having hiccups in the morning, which lasted after 3–4 hours. As a result, aripiprazole was discontinued and methylphenidate was continued alone because we could not convince the patient to use another additional drug due to this side effect. Subsequently, when his behavior got worsened day by day, his mother administered aripiprazole alone again at the dose of 2.5 mg/day at the weekend and continued treatment because hiccup did not occur again. But when it was administered with methylphenidate on Monday, hiccup started again next morning and lasted one hour at this time. In conclusion, we concluded that concurrent use of methylphenidate and aripiprazole in this adolescent led to hiccups.
Adolescent*
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Antipsychotic Agents
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Aripiprazole*
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Conduct Disorder*
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Cytochrome P-450 CYP2D6
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Hiccup*
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Humans
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Male
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Methylphenidate*
;
Mothers
7.Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine.
Psychiatry Investigation 2012;9(4):422-424
I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy.
Aged
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Cytochrome P-450 CYP2D6
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Female
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Humans
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Naphthalenes
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Perphenazine
;
Psychomotor Agitation
8.In vitro O-demethylation of rotundine by recombinant human CYP isoenzymes.
Chun-zheng LI ; Qing-hui LIN ; Xiao-mei ZHUANG ; Jian-wei XIE ; Hua LI
Acta Pharmaceutica Sinica 2010;45(3):307-313
Rotundine (1 micromol L(-1)) was incubated with a panel of rCYP enzymes (1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The remained parent drug in incubates was quantitatively analyzed by an Agilent LC-MS. CYP2C19, 3A4 and 2D6 were identified to be the isoenzymes involved in the metabolism of rotundine. The individual contributions of CYP2C19, 3A4 and 2D6 to the rotundine metabolism were assessed using the method of total normalized rate to be 31.46%, 60.37% and 8.17%, respectively. The metabolites of rotundine in incubates were screened with ESI-MS at selected ion mode, and were further identified using MS2 spectra and precise molecular mass obtained from an Agilent LC/Q-TOF-MSMS, as well as MS(n) spectra of LC-iTrap-MS(n). The predominant metabolic pathway of rotundine in rCYP incubates was O-demethylation. A total 5 metabolites were identified including 4 isomerides of mono demethylated rotundine and one di-demethylated metabolite. The results also showed that CYP2C19, 2D6 and 3A4 mediated O-demethylation of methoxyl groups at different positions of rotundine. Furthermore, the ESI-MS cleavage patterns of rotundine and its metabolites were explored by using LC/Q-TOF-MSMS and LC/iTrap-MS(n) techniques.
Analgesics, Non-Narcotic
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metabolism
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Aryl Hydrocarbon Hydroxylases
;
metabolism
;
Berberine Alkaloids
;
metabolism
;
Chromatography, Liquid
;
Cytochrome P-450 CYP1A2
;
metabolism
;
Cytochrome P-450 CYP2C19
;
Cytochrome P-450 CYP2C9
;
Cytochrome P-450 CYP2D6
;
metabolism
;
Cytochrome P-450 CYP3A
;
metabolism
;
Cytochrome P-450 Enzyme System
;
metabolism
;
Dopamine Antagonists
;
metabolism
;
Humans
;
Isoenzymes
;
metabolism
;
Methylation
;
Recombinant Proteins
;
metabolism
;
Spectrometry, Mass, Electrospray Ionization
9.Correlation between Genetic Polymorphism of CYP2D6 and CYP1A1 and Susceptibility of Renal Cell Carcinoma in Korean.
Kyu Wook PARK ; Se Il JUNG ; Gyung Woo JUNG ; Heon Young KWON ; Jin Sook JEONG ; Jin Ho CHUN ; Jin Han YOON
Journal of the Korean Cancer Association 2000;32(4):801-809
PURPOSE: Many of the enzymes handling environmental factors are polymorphic and may confer variable susceptibility to renal cell carcinoma (RCC). Among those, the author studied genetic polymorphisms of CYP2D6 (B & T) and CYP1A1 in RCCs and controls in Korean. MATERIALS AND METHODS: Using 132 RCCs and 94 controls, first PCR products were obtained in 104 RCCs and 94 controls with CYP2D6, and 74 RCCs and 56 controls with CYP1A1. Res triction enzyme - BstN I/EcoN I for CYP2D6 (B & T), and NCo I for CYP1A1-digestion was followed to analyze constitutive DNA. RESULTS: In both RCCs and controls, no mutant allele of CYP2D6 (B & T) was detected and the susceptibility for occurrence of RCC was unable to evaluate. With CYP1A1 RFLP, homozy gous wild type (WW) was seen in 68 (52.3%; 37 RCCs, 31 controls), heterozygous mutant type (WM) in 54 (41.5%; 32 RCCs, 22 controls) and homozygous mutant type (MM) in 8 (6.2%; 5 RCCs, 3 controls). The odds ratios (95% CI) of RCC susceptibility for CYP1A1 genotype were 1.15 for WM and 1.36 for MM. Even though not significant statistically, higher tendency in MM presented. CONCLUSION: There is no association between susceptibility for the occurrence of RCC and genetic polymorphism of CYP2D6 (B & T) and CYP1A1.
Alleles
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Carcinoma, Renal Cell*
;
Cytochrome P-450 CYP1A1*
;
Cytochrome P-450 CYP2D6*
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DNA
;
Genotype
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Odds Ratio
;
Polymerase Chain Reaction
;
Polymorphism, Genetic*
;
Polymorphism, Restriction Fragment Length
10.Genetic polymorphisms of CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in Vietnamese-Koreans.
Ye Ji LIM ; Eun Young CHA ; Hye Eun JUNG ; Jong Lyul GHIM ; Su Jun LEE ; Eun Young KIM ; Jae Gook SHIN
Translational and Clinical Pharmacology 2014;22(2):70-77
The Vietnamese-Koreans, especially offspring between a Vietnamese mother and a Korean father constituted the highest proportion (64.2%) of total Kosian population according to a census in 2014. To evaluate genetic characteristics in the Vietnamese-Koreans, a total of 25 alleles from CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were genotyped using SNaPshot method with DNA samples of 127 Vietnamese-Koreans. The previous reports on the CYPs of Korean and Vietnamese populations were also analyzed for the comparative studies for the frequencies of CYP alleles. The statistical significances in allele and genotype frequencies among the ethnics were analyzed by Chi-square or Fisher's exact probability test. Although most of variants analyzed in 5 CYPs did not reach the statistically significant difference between the Vietnamese-Koreans and Vietnamese, some alleles were only found in Vietnamese-Koreans. Compared with Korean population, frequencies of CYP2D6*1 and CYP2D6*10B were statistically different from Vietnamese-Koreans (p<0.05). This is the first report to describe the CYP genotype profiles of Vietnamese-Koreans, which may provide important insight for the genotype based prediction of CYP activities of this admixture of Korean and Vietnamese.
Alleles
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Asian Continental Ancestry Group
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Censuses
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Cytochrome P-450 CYP2D6*
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Cytochrome P-450 Enzyme System
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DNA
;
Fathers
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Genotype
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Humans
;
Mothers
;
Polymorphism, Genetic*