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
;
China
;
Cytochrome P-450 CYP2D6
;
genetics
;
Humans
;
Polymorphism, Genetic
2.The relationship between genetic polymorphism of metabolizing enzymes and the genetic susceptibility to lung cancer.
Wei-Ying LI ; Bai-Tang LAI ; Xiu-Ping ZHAN
Chinese Journal of Epidemiology 2004;25(12):1042-1045
<p>OBJECTIVETo investigate the relationship between the gene polymorphism of metabolizing enzymes and the genetic susceptibility to lung cancer as well as to study the synergistic effects between smoking and the genes.p><p>METHODSA case-control study (case = 217, control = 200) was carried out to compare the frequent distribution of CYP1A1, 2E1, 2D6 and GSTM1 genotypes between the lung cancer group and the control group with a polymerase chain reaction-restriction fragment polymorphism (PCR-RFLP) method and to analyze the relationship between these genes and smoking.p><p>RESULTSGSTM1-null genotype frequency was 58.5% in the lung cancer group and 47.5% in the control group with significant difference (P = 0.02). The frequent distribution of CYP1A1, 2E1, 2D6 genotypes was not significantly different in the two groups (P > 0.05). Synergistic effects were found between smoking and GSTM1 but not between smoking and CYP1A1, 2E1, 2D6.p><p>CONCLUSIONSmoking and GSTM1-null genotype seemed to be the risk factors of lung cancer. Those who carrying GSTM1-null genotype and smoking cigarettes were prone to suffer from lung cancer to become the high-risk population of the disease.p>
Cytochrome P-450 CYP1A1
;
genetics
;
Cytochrome P-450 CYP2D6
;
genetics
;
Genetic Predisposition to Disease
;
genetics
;
Glutathione Transferase
;
biosynthesis
;
genetics
;
Homozygote
;
Humans
;
Lung Neoplasms
;
genetics
;
Male
;
Polymorphism, Genetic
3.No association between cytochrome P450 2D6 gene polymorphism and risk of acute leukemia: evidence based on a meta-analysis.
Xiao-lan RUAN ; Sheng LI ; Xian-tao ZENG ; Ling-hui XIA ; Yu HU
Chinese Medical Journal 2013;126(19):3750-3753
<p>BACKGROUNDMany studies indicated the human cytochrome P450 2D6 (CYP2D6) gene polymorphism was associated with acute leukemia (AL) susceptibility, however, the results were inconsistent. So we performed this meta-analysis to evaluate the relationship between CYP2D6*3 or CYP2D6*4 polymorphism and AL susceptibility.p><p>METHODSWe searched PubMed database up to February 20, 2013, and finally yielded 9 case-control studies including 1343 cases and 1843 controls which tested the association between CYP2D6*3 or *4 polymorphism and AL. After data extraction, we conducted a meta-analysis using the Comprehensive Meta Analysis software.p><p>RESULTSOverall, no significant association between CYP2D6*3 or *4 polymorphism and AL risk was found in this metaanalysis (+ vs. -: OR = 1.13, 95% CI = 0.79-1.63; +/+ vs. -/-: OR = 1.73, 95% CI = 0.99-3.02; -/+ vs. -/-: OR = 1.03, 95% CI = 0.68-1.56; (-/+ and +/+) vs. -/-: OR = 1.08, 95% CI = 0.72-1.63; +/+ vs. (-/+ and -/-): OR = 1.76, 95% CI = 0.98-3.17). Similar results were also been found in stratified subgroup analysis. There was no publication bias.p><p>CONCLUSIONCYP2D6*3 or *4 polymorphism might not be associated with AL susceptibility. However, the results need to be further confirmed by well-designed and high quality randomized controlled trials with larger sample sizes.p>
Acute Disease
;
Cytochrome P-450 CYP2D6
;
genetics
;
Genetic Predisposition to Disease
;
Humans
;
Leukemia
;
etiology
;
genetics
;
Polymorphism, Genetic
;
Risk
4.Genetic polymorphism of CYP-1A1, CYP2D6 and risks of chronic benzene poisoning.
Shou-yong GU ; Zhong-bin ZHANG ; Duo-zhi CAO ; Jun-xiang WAN ; Xiao-ling GAO ; Xi-peng JIN ; Zhao-lin XIA
Chinese Journal of Industrial Hygiene and Occupational Diseases 2006;24(5):266-269
<p>OBJECTIVETo explore the relationship between genetic polymorphisms of CYP-1A1 and CYP2D6 and risks of chronic benzene poisoning (BP).p><p>METHODSA case control study was conducted. 152 BP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were involved. Polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) technology was used for detecting the single nucleotide polymorphisms (SNPs) of MspI in the non-coding region of CYP-1A1 gene and c.188, g.212 position in the first extron of CYP2D6 gene.p><p>RESULTSThe individuals with CYP1A1 MspI T/T genotype had a 1.32 times (95% CI: 1.05 approximately 1.65, P = 0.02) increased risk of BP compared with those carrying T/C and C/C genotypes. In no-smoking population, there was a 1.56 times (95% CI: 1.15 approximately 2.12, P = 0.003) increased risk of BP for subjects carrying CYP1A1 MspIT/T genotype compared with those carrying T/C and C/C genotypes. The individuals carrying CYP2D6 c.188 C/C or C/T genotype had a 1.23 times (95% CI: 1.05 approximately 1.42, P = 0.01) increased risk compared with those carrying T/T genotypes. In no-smoking population, there was a 1.23 times (95% CI: 1.04 approximately 1.47, P = 0.01) increased risk of BP for subjects carrying CYP2D6 c.188 C/C or C/T genotypes compared with those carrying T/T genotype. The single nucleotide polymorphism of g.212 position in the first extron of CYP2D6 gene had not been validated.p><p>CONCLUSIONThe individuals with CYP2D6 c.188 C/C, CYP2D6 c.188 C/T and CYP1A1 MspIT/T genotypes tend to be more susceptible to benzene toxicity.p>
Adolescent
;
Adult
;
Benzene
;
poisoning
;
Case-Control Studies
;
Chronic Disease
;
Cytochrome P-450 CYP1A1
;
genetics
;
Cytochrome P-450 CYP2D6
;
genetics
;
Female
;
Genetic Predisposition to Disease
;
Genotype
;
Humans
;
Male
;
Middle Aged
;
Occupational Diseases
;
genetics
;
Polymerase Chain Reaction
;
Polymorphism, Restriction Fragment Length
5.pharmacogenomics and Schizophrenia.
Journal of the Korean Society of Biological Psychiatry 2001;8(2):208-219
The pharmacotherapy of schizophrenia exhibit wide inter-individual variabilities in clinical efficacy and adverse effects. Recently. human genetic diversity has been known as one of the essential factors to the variation in human drug response. This suggests that drug therapy should be tailored to the genetic characteristics of the individual. Pharmacogenetics is the field of investigation that attempts to elucidate genetic basis of an individual's responses to pharmacotherapy, considering drug effects divided into two categories as pharmacokinetics and pharmacodynamics. The emerging field of pharmacogenomics. which focuses on genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually tailored drugs and will aid in understanding how genetics influence drug response. In schizophrenia, pharmacogenetic studies have shown the role of genetic variants of the cytochrome P450 enzymes such as CYP2D6, CYP2C19, and CYP2A1 in the metabolism of antipsychotic drugs. At the level of drug targets, variants of the dopamine D_(2), D_(3) and D_(4), and 5-HT_(2A) and 5-HT(2C) receptors have been examined. The pharmacogenetic studies in schizophrenia presently shows controversial findings which may be related to the multiple involvement of genes with relatively small effects and to the lack of standardized phenotypes. For further development in the pharmacogenomics of schizophrenia, there would be required the extensive outcome measures and definitious, and the powerful new tools of genomics, proteomics and so on.
Antipsychotic Agents
;
Cytochrome P-450 CYP2D6
;
Cytochrome P-450 Enzyme System
;
Dopamine
;
Drug Therapy
;
Genetic Variation
;
Genetics
;
Genome, Human
;
Genomics
;
Humans
;
Metabolism
;
Outcome Assessment (Health Care)
;
Pharmacogenetics*
;
Pharmacokinetics
;
Phenotype
;
Prescriptions
;
Proteomics
;
Receptor, Serotonin, 5-HT2C
;
Receptors, Dopamine
;
Schizophrenia*
6.A Case Report of a Poor Metabolizer of CYP2D6 Presented with Unusual Responses to Nortriptyline Medication.
Soo Youn LEE ; Chang Seok KI ; Kyung Sue HONG ; Jong Won KIM
Journal of Korean Medical Science 2004;19(5):750-752
We present a case with decreased metabolic activity of CYP2D6, a cytochrome P450 enzyme catalyzing the metabolism of nortriptyline (NT). Conventional dosage regimen led to toxic plasma concentration of NT and adverse effects such as dry mouth, constipation, and dizziness in this case with genotype CYP2D6*5/*10B. This case suggests the clinical usefulness of pharmacogenetic testing in individualized dosage adjustments of NT.
Antidepressive Agents, Tricyclic/*adverse effects/pharmacokinetics
;
Cytochrome P-450 CYP2D6/*genetics/metabolism
;
Depression/*drug therapy/genetics
;
Genotype
;
Humans
;
Male
;
Middle Aged
;
Nortriptyline/*adverse effects/pharmacokinetics
7.Association analysis of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning based on logistic regression and multifactor dimensionality reduction.
Ru-Feng JIN ; Jun-Xiang WAN ; Shou-Yong GU ; Pin SUN ; Zhong-Bin ZHANG ; Xi-Peng JIN ; Zhao-Lin XIA
Chinese Journal of Industrial Hygiene and Occupational Diseases 2011;29(7):481-486
<p>OBJECTIVETo explore the association of polymorphisms of metabolizing enzyme genes with chronic benzene poisoning (CBP) comprehensively by case-control design.p><p>METHODS152 CBP patients and 152 workers occupationally exposed to benzene without poisoning manifestations were investigated. 30 single nucleotide polymorphisms (SNPs) in 13 genes such as CYP2E1 were tested by PCR-RFLP, sequencing approaches. Logistic regression model was used to detect main effects and 2-order interaction effects of gene and/or environment. Multifactor dimensionality reduction (MDR) was used to detect high-order gene-gene or gene-environment interactions.p><p>RESULTSBased on logistic regression, the main effects of GSTP1 rs947894, EPHX1 rs1051740, CYP1A1 rs4646903, CYP2D6 rs1065852 and rs1135840 were found to be significant (P < 0.05) while the confounding factors of sex, cigarette smoking, alcohol consumption and the intensity of benzene exposure were controlled. EPHX1 rs1051740 might be associated with CBP (P = 0.06). There existed 3 types of interactions were as followed: interactions of GSTP1 rs947894 with alcohol consumption, CYP2E1 rs3813867 with EPHX1 rs3738047, EPHX1 rs3738047 with alcohol consumption(P < 0.05), while the main effects of CYP2E1 rs3813867 and EPHX1 rs3738047 were not significant (P > 0.05). The other SNPs did not show any significant associations with CBP. According to MDR, a 3-order interaction with the strongest combined effect was found, i.e. the 3-factor combination of CYP1A1 rs4646903, CYP2D6 rs1065852 and CYP2D6 rs1135840.p><p>CONCLUSIONGene-gene, gene-environment interactions are important mechanism to genetic susceptibility of CBP.p>
Adult
;
Benzene
;
poisoning
;
Case-Control Studies
;
Cytochrome P-450 CYP1A1
;
genetics
;
Cytochrome P-450 CYP2D6
;
genetics
;
Cytochrome P-450 CYP2E1
;
genetics
;
Epoxide Hydrolases
;
genetics
;
Female
;
Gene-Environment Interaction
;
Genetic Predisposition to Disease
;
Genotype
;
Humans
;
Logistic Models
;
Male
;
Middle Aged
;
Multifactor Dimensionality Reduction
;
Occupational Exposure
;
Polymorphism, Single Nucleotide
;
Young Adult
8.CYP2D6*10 polymorphisms and lung cancer susceptibility.
Zhen YAN ; Yi-Ming WU ; Yong-Jun WU
Acta Academiae Medicinae Sinicae 2008;30(5):564-568
<p>OBJECTIVETo analyze the correlation between the polymorphism of CYP2D6*10 allele and the risk of lung cancer.p><p>METHODSA case-control study was conducted among 118 lung cancer patients and 118 control subjects (matched for sex and age) to investigate the role of the single nucleotide polymorphism of C188T and G4268C in lung cancer using PCR-RFLP to identify the genotypes. Logistic regression was taken to analyze the relationship between genetic polymorphism and lung cancer susceptibility and evaluate the combined effect of genotypes and smoking.p><p>RESULTSThe non-T188/T genotype (including C188/C and C188/T genotype) or non-C4268/C genotype (including G4268/G and G4268/C genotype) was moderately correlated with lung cancer. After stratification analysis according to smoking, it revealed that non-T188/T or non-C4268/C genotype was associated with significantly increased risk in non-smokers and light-smokers subgroups; however, there was no interaction between non-T188/T or non-C4268/C genotype and smoking on susceptibility to lung cancer, neither between the two genotypes.p><p>CONCLUSIONT188/T or C4268/C genotype, as protective factors in non-smokers or light-smokers subgroups, may help decrease the susceptibility to lung cancer in these subjects.p>
Aged
;
Asian Continental Ancestry Group
;
genetics
;
Case-Control Studies
;
China
;
Cytochrome P-450 CYP2D6
;
genetics
;
Female
;
Genetic Predisposition to Disease
;
Genotype
;
Humans
;
Lung Neoplasms
;
genetics
;
Male
;
Middle Aged
;
Polymorphism, Single Nucleotide
;
Risk Factors
;
Smoking
;
genetics
9.CYP2D6*1, CYP2D6*10 co-expressed with CYPOR in Bac-to-Bac expression system and activity determination.
Ming-rong QIAN ; Jing CHEN ; Yao LIU ; Lu-shan YU ; Shu-qing CHEN ; Su ZENG
Acta Pharmaceutica Sinica 2011;46(2):207-212
CYP2D6 is an important drug-metabolizing enzyme. The polymorphism of CYP2D6 leads to metabolism difference and the different reactions of drugs in the individuals and different races are normal phenomenon in clinical medication. CYP2D6*10 is an important subtype in Asian people and 51.3% Chinese are classified with this subtype. To obtain recombinant active CYP2D6*1/CYP2D6*10 in baculovirus system by optimizing coexpression with CYPOR, and detect their activity to catalyze dextromethorphan, three recombinants pFastBac-CYP2D6*1, pFastBac-CYP2D6*10 and pFastBac-CYPOR were constructed and transformed into DH10Bac cell to obtain the recombinant Bacmid-CYPOR, Bacmid-CYP2D6*1 and Bacmid-CYP2D6*10. And then the recombinant CYP2D6*1 and CYP2D6*10 virus were obtained by transfecting Sf9. Then homogenate protein activity was determined with dextromethorphan as substrate. The multiple of infection (MOI) and its ratio of recombinant CYP2D6 virus to CYPOR virus were adjusted by detecting the activity of the homogenate protein. The Km and Vmax are 26.67 +/- 2.71 micromol x L(-1) (n=3) and 666.7 +/- 56.78 pmol x nmol(-1) (CYP2D6) x min(-1) (n=3) for CYP2D6*1 to catalyze dextromethaphan. The Km and Vmax are 111.36 +/- 10.89 micromol x L(-1) (n=3) and 222.2 +/- 20.12 pmol x nmol(-1) (CYP2D6) x min(-1) (n=3) for CYP2D6*10 to catalyze dextromethorphan. There is significant difference between CYP2D6*1 and CYP2D6*10 for Vmax and Km (P < 0.01). The clearance ratio of CYP2D6*1 is 25.0 and the clearance ratio of CYP2D6*10 is 2.0. The expressed CYP2D6*1 and CYP2D6*10 are useful tools to screen the metabolism profile of many xenobiotics and endobiotics in vitro, which are benefit to understand individual metabolism difference.
Animals
;
Baculoviridae
;
enzymology
;
genetics
;
Catalysis
;
Cells, Cultured
;
Chromatography, High Pressure Liquid
;
methods
;
Cytochrome P-450 CYP2D6
;
genetics
;
metabolism
;
Dextromethorphan
;
metabolism
;
Isoenzymes
;
metabolism
;
NADPH-Ferrihemoprotein Reductase
;
genetics
;
metabolism
;
Plasmids
;
Recombinant Proteins
;
genetics
;
metabolism
;
Spectrometry, Mass, Electrospray Ionization
;
Spodoptera
;
cytology
;
virology
;
Transfection
10.Relationships between the gene polymorphisms of drug metabolizing enzymes and the outcome of the first induction chemotherapy in patients with de novo acute myeloid leukemia.
Na WANG ; Jun-Ling HAN ; Ying-Chang MI ; Zhi-Jian XIAO ; Si-Zhou FENG ; Yu-Ling ZHOU ; Jian-Xiang WANG ; Ming-Zhe HAN
Journal of Experimental Hematology 2011;19(2):327-331
The objective of this study was to investigate the correlation between the gene polymorphisms of drug metabolizing enzymes and the outcome of the first induction chemotherapy in patients with de novo acute myeloid leukemia (AML). 113 de novo AML patients were enrolled in this study. The genotypes of 11 single nucleotide polymorphisms (SNP) in drug metabolizing enzymes were detected by the SNPstream(®) Genotyping System. The correlation between the distribution of genotypes and the complete remission rate of first induction chemotherapy was analyzed by logical regression. The results showed that patients with variant genotype of CYP2D6 (rs16947) had a lower complete remission (CR) rate, as compared to those with wild type (p = 0.033, OR = 0.32, 95%CI 0.112 - 0.915); meanwhile the patients with variant genotype of GSTO2 (rs156697) had a higher CR rate as compared to those with wild type (p = 0.011, OR = 3.023, 95%CI 1.289 - 7.089). Combined analysis of the above polymorphisms, showed that patients with variant genotype of CYP2D6 and wild genotype of GSTO2 (V + W) had lower CR rates in comparison to patients with wild genotypes of both polymorphisms (p = 0.017, OR = 0.183, 95%CI 0.045 - 0.735). It is concluded that CYP2D6 (rs16947) and GSTO2 (rs156697) polymorphisms are independent factors influencing CR rates of the first induction chemotherapy in de novo AML patients.
Adolescent
;
Adult
;
Aged
;
Antineoplastic Agents
;
therapeutic use
;
Child
;
Cytochrome P-450 CYP2D6
;
genetics
;
Female
;
Genotype
;
Glutathione Transferase
;
genetics
;
Humans
;
Leukemia, Myeloid, Acute
;
drug therapy
;
enzymology
;
genetics
;
Male
;
Middle Aged
;
Polymorphism, Single Nucleotide
;
Remission Induction
;
Treatment Outcome
;
Young Adult