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PubMed2006

Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation.

1. The calcineurin inhibitor cyclosporine is widely used to prevent allograft rejection after solid organ transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual differences in the activity and expression of the metabolising enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp) contribute considerably to cyclosporine pharmacokinetics. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes. 2. The aim of the present study was to evaluate retrospectively the effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine dose adjusted trough blood concentration during the early period after renal transplantation in Chinese patients. 3. One hundred and six renal transplant recipients in China were genotyped by polymerase chain reaction-restriction fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and MDR1 C3435T. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Dose-adjusted trough blood concentrations (C(0)) were determined and compared among the different genotype groups. 4. The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T variant alleles were 0.005 (95% confidence interval (CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95% CI 0.526, 0.531), respectively, and these alleles exhibited incomplete linkage disequilibrium. The median cyclosporine dose-adjusted C(0) in CYP3A5*1/*1 genotype subjects (n = 6) was 14.8 ng/mL per mg per kg (range 11.1-26.8 ng/mL per mg per kg), in CYP3A5*1/*3 patients (n = 34) it was 23.7 ng/mL per mg per kg (range 9.0-61.0 ng/mL per mg per kg) and for CYP3A5*3/*3 patients (n = 66) it was 26.4 ng/mL per mg per kg (range 9.8-85.8 ng/mL per mg per kg; P = 0.012, Kruskal-Wallis test). Accordingly, cyclosporine dose-adjusted C0 was larger in CYP3A5 non-expressors than expressors in the first week after renal transplantation. In addition, wild-type homozygotes (n = 21) for MDR1 C3435T had a slight but significantly lower dose-adjusted C0 compared with heterozygotes (n = 58): 17.7 (10.3-60.8) versus 26.4 (9.0-67.3) ng/mL per mg per kg, respectively (P = 0.014, Mann-Whitney U-test). 5. In conclusion, the present study shows that genetic polymorphisms in CYP3A5 may be responsible, in part, for the large interindividual variability of cyclosporine pharmacokinetics during the early phase after renal transplantation in Chinese patients. Patients with the CYP3A5*3 variant genotype require a low dose of cyclosporine to reach target levels compared with those with the CYP3A5*1 allele.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[Genetic polymorphisms in xenobiotic metabolizing enzymes as a determinant of susceptibility to environmental mutagens and carcinogens in humans].

Xenobiotic metabolizing enzymes are known to play a role in the metabolic activation of environmental mutagens and carcinogens to exert their carcinogenic effects as well as detoxification by increasing their hydrophilicity. These enzymes include cytochrome P450s, glutathione S-transferases (GSTs), acetyltransferases (NATs) and sulfotransferases. Genetic polymorphisms in many of these enzymes, such as CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1, GSTP1 and GSTT1, have been shown to occur, which result in the altered expression of enzymatic activities. This suggests that the genetic polymorphisms may affect the individual susceptibility to environmental carcinogens and thus play a role in human carcinogenesis. Recently, the mutations that confer those polymorphisms of xenobiotic metabolizing enzymes have been identified and genotyping methods for the genetic polymorphisms have been developed. Specific phenotypes and genotypes for CYP1A1, CYP2D6, CYP2E1, NAT1, NAT2, GSTM1 and GSTP1 have been associated with susceptibility to malignant diseases including lung, bladder and colon cancers, although the association was not confirmed in some studies. A number of factors such as degree of exposure to environmental carcinogens and the role of xenobiotic metabolizing enzymes in human carcinogenesis should carefully be evaluated in understanding genetic susceptibility.

Acetyltransferases↗
PubMed2004

Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population.

Helicobacter pylori infection and the cytokine-mediated inflammatory responses play important roles in gastric cancer pathogenesis. This case control study was conducted to assess the association between genetic polymorphisms in interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor alpha (TNFalpha), which are involved in H.pylori infection, and risk of gastric cancer. Genotypes were determined by PCR-based denaturing high-performance liquid chromatography analysis and direct DNA sequencing in 250 incident cases with gastric cancer and 300 controls recruited in Northern China. Serum levels of anti-H.pylori IgG and IgA were measured by enzyme-linked immunosorbent assay to indicate H.pylori infection. We found that the risk of gastric cancer was significantly elevated in subjects with the IL-8-251 AA [adjusted odds ratio (OR) 2.02; 95% confidence interval (CI) 1.27-3.21] or IL-10-1082 G (OR 2.02; 95% CI 1.24-3.29) or TNFalpha-308 AG (OR 1.81; 95% CI 1.04-3.14) genotype. An elevated risk of gastric cancer was observed in subjects with H.pylori infection and the IL-8-251 AA genotype (OR 2.54; 95% CI 1.38-4.72) or IL-10-1082 G carriers (OR 2.62; 95% CI 1.42-4.93). An increased OR was also suggested for IL-1B-31 and TNFalpha-238, but confidence intervals included the null value. There was no evidence of increased risk for any of the other polymorphisms evaluated. These findings suggest that genetic polymorphisms in IL-8, IL-10 and TNFalpha may play important roles in developing gastric cancer in the Chinese population.

Adult↗
PubMed1996

Genetic polymorphism of GSTM1, CYP2E1 and CYP2D6 in Egyptian bladder cancer patients.

Polymorphic changes in the GSTM1, CYP2E1 and the CYP2D6 genes have been reported to be individually associated with increased susceptibility to certain cancers. In the present study, the relationship between genetic polymorphism for these genes and development of urinary bladder cancer among Egyptian patients was investigated. Our results indicate that the frequency of bladder cancer patients with the GSTM1 null genotype is significantly higher than that of the normal controls (86.3 and 47.6%, respectively) with an odds ratio (OR) of 6.97 (95% CL -1.59-30.57, Fisher's exact P = 0.008). In contrast, our investigation failed to demonstrate any difference in the distribution of CYP2E1 polymorphism between bladder cancer patients and controls as detected by PstI restriction fragment length polymorphism (RFLP) analysis. RFLP analysis of the CYP2D6 gene revealed a non-significant increase in the number of extensive metabolizers (EM) among the patients compared to the controls (68 versus 48%). However, the EM genotypes enhances the risk further for individuals harboring the GSTM1 null genotype as individuals harboring both the EM and the GSTM1 null genotypes have an odds ratio of 14.0 (95% CL = 1.3- 151.4, Fisher's exact P = 0.02) compared to individuals harboring the EM and the GSTM1 +/+ genotypes. In conclusion, our results indicate that genetic polymorphism, especially in GSTM1 and CYP2D6 could play an important role as host risk factors for development of urinary bladder cancer among Egyptians.

Base Sequence↗
PubMed2006

[Relationship between paraoxonase 1 55 Met/Leu, paraoxonase 2 148 Ala/Gly genetic polymorphisms and coronary artery disease].

OBJECTIVE: To study the relationships between paraoxonase 1 55 Met/Leu (PON1 55Met/Leu), paraoxonase 2 148 Ala/Gly(PON2 148Ala/Gly) genetic polymorphisms and coronary artery disease(CAD), plasma activities of paraoxonase (PON), total superoxide dismutase (T-SOD), as well as plasma concentration of maleic dialdehyde (MDA). METHODS: The PCR-RFLP method was applied to identify the genetic polymorphisms of PON1 55Met/Leu and PON2 148Ala/Gly, and the colorimetry way was used to detect plasma activities of PON, T-SOD and plasma MDA concentration of 262 CAD patients and 100 controls. RESULTS: Comparing with control, the CAD patient had the obviously lower activities of enzymes PON (349.27+/- 138.36 nmol/min.mL vs 454.75+/- 166.00 nmol/min.mL, P< 0.001) and T-SOD (23.61+/- 16.51 U/mL vs 44.01+/- 22.68 U/mL, P< 0.001) while getting the plasma MDA concentration increased markedly(2.47+/- 0.73 nmol/mL vs2.15+/- 0.55 nmol/mL, P< 0.01). The CAD patient had more LM genotype and M allele of PON1 55Met/Leu(24.8% vs 1.4%, P< 0.001 and 12.4% vs 0.5%, P was 0.001 respectively), GG and AG genotype and G allele of PON2 148 Ala/Gly(11.8% vs 5.0%, P< 0.001; 48.1% vs 24.0%, P< 0.001 and 36.0% vs 17.0%, P< 0.001 respectively) than control did. The activities of plasma PON and T-SOD were lower in individuals with PON??1 55 LM genotype than those with LL genotype(304.73+/- 125.04 vs 394.84+/- 154.87 nmol/min.mL and 24.89+/- 16.14 vs 30.22+/- 21.29 U/mL, P< 0.001 and P< 0.05 respectively). The activity of plasma PON was also lower in individuals with PON2 148 GG/AG genotype than that with AA genotype(281.47+/- 84.70 vs 356.00+/- 145.95 vs 417.34+/- 159.00 nmol/min.mL, P< 0.001). Logistic regression analysis showed that PON1 55 LM genotype (OR 29.08, 95%CI 2.88-294.04, P was 0.004) and M allele(OR 15.17, 95%CI 1.32-174.29, P was 0.029), PON2 148 GG/AG genotype (OR 2.32, 95%CI 1.52-3.54, P< 0. 001) and G allele (OR 3.24, 95%CI 1.38-7.61, P was 0.007) were independent risk factors for CAD. CONCLUSION: The CAD patient has the obviously low activities of plasma PON and T-SOD but on the contrary, get the plasma MDA concentration increased markedly. PON1 55 LM genotype and M allele, PON2 148 GG/AG genotype and G allele are the risk factors for coronary artery disease, and the activity of plasma PON is also markedly reduced in individuals with above genotypes.

Adult↗
PubMed2002

Interindividual differences in nicotine metabolism and genetic polymorphisms of human CYP2A6.

Nicotine is widely consumed throughout the world, and exerts a number of physiological effects. After nicotine is absorbed through the lungs by cigarette smoking, it undergoes extensive metabolism in humans. Nicotine is mainly metabolized to cotinine by cytochrome P450 (CYP) 2A6. CYP2A6 can metabolize some pharmaceutical agents such as halothane, valproic acid, and fadrozole, and activate tobacco-specific nitrosamines. There are large interindividual differences in nicotine metabolism, and it has been found that the interindividual differences are attributed to the genetic polymorphisms of CYP2A6 gene. This review describes the techniques for determination of in vivo nicotine metabolism, characteristics of each human CYP2A6 alleles, and ethnic differences. The relationship between CYP2A6 genetic polymorphism and potency of nicotine metabolism, smoking behavior, and cancer risk are extensively reviewed. Finally, the usefulness of nicotine metabolism for phenotyping of CYP2A6 in individuals and implication of the significance of CYP2A6 genetic polymorphism in a clinical perspective are discussed.

Animals↗
PubMed2004

Genetic polymorphisms in the TGF-beta 1 gene and breast cancer survival: a report from the Shanghai Breast Cancer Study.

The effect of genetic polymorphisms in the TGF-beta1 gene at codon 10 (T+29C), codon 25 (G+74C), and the promoter region [C --> T at -509 from the transcription site, (C-509T)] on breast cancer survival was evaluated among a cohort of 1111 patients. The median follow-up time for the cohort was 5.17 years after cancer diagnosis. No DNA sequence variation at codon 25 of the TGF-beta1 gene was found, whereas polymorphisms in C-509T and T+29C were in strong linkage disequilibrium. Patients who carried the C allele of T+29C polymorphism had a reduced 5-year disease-free survival rate (75.6% for T/C, and 78.2% for C/C) compared with the T/T genotype (85.1%; P, 0.04); the age-adjusted hazard ratio was 1.5 (95% confidence interval, 1.1-2.2). Adjustment for clinical prognostic factors slightly attenuated the association (hazard ratio, 1.4, 95% confidence interval, 1.0-1.9). Our study suggests that genetic polymorphisms in the TGF-beta1 gene may play a role in breast cancer progression.

Adult↗
PubMed1997

Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy.

OBJECTIVE: To examine the genetic polymorphism of CYP2C9 and CYP2C19 and its effect on the pharmacokinetics of phenytoin among 44 Japanese patients with epilepsy. METHODS: Polymerase chain reaction tests with leukocyte deoxyribonucleic acid were used to detect the mutations for the amino acid substitution (Arg144-->Cys and Ile359-->Leu) in CgammaP2C9 and for the defective allele (m1 and m2) in CgammaP2C19. The pharmacokinetic parameters of phenytoin in individual patients were estimated by means of empirical bayesian analysis, in which the prior information was the population parameters for Japanese patients with epilepsy. RESULTS: Of the 44 patients, none had the CgammaP2C9 mutation for the Cys144 allele, whereas six patients were heterozygous for the wild-type (wt) and Leu359 allele (wt/Leu359) in cgammaP2C9. The maximal elimination rate (Vmax) of phenytoin among patients with heterozygous wt/Leu359 in CgammaP2C9 was 33% lower than that among patients with normal CgammaP2C9. A total of 21 patients were heterozygous for the CgammaP2C19 mutation (wt/m1 or wt/m2), and five patients had the homozygous or heterozygous mutations in CgammaP2C19 (m1/m1 or m1/m2). The Vmax values of phenytoin were slightly decreased (up to 14%) among patients with CgammaP2C19 mutations compared with patients with normal CgammaP2C19. CONCLUSION: The findings indicated that the genetic polymorphisms of CYP2C isozymes play an important role in the pharmacokinetic variability of phenytoin and that the mutation in CYP2C9 proteins (Ile359-->Leu) is a determinant of impaired metabolism of the drug among Japanese persons.

Adolescent↗
PubMedDate not supplied

[Influence of genetic polymorphism of CYP1A1 and GSTM1 on the levels of urinary 1-hydroxypyrene].

In recent years scientific literature has focused the attention on the role of genetic polymorphisms and toxic effects of xenobiotics. Polycyclic Aromatic Hydrocarbons (PAHs) are widely spread xenobiotics, present both in general and work environment. Many papers analysed the influence of the genetic polymorphism of two enzymes involved in the biotransformation of PAHs, Cytochrome P450 1A1 (CYP1A1) and Glutathione S Transferase M1 (GSTM1), on the development of cancer. Some papers analysed also the role of these polymorphisms on the concentration of the biomarker of exposure to PAHs, 1-hydroxypyrene (1OHP). The Institute of Occupational Health and Industrial Hygiene of the University of Brescia focused on this last aspect by EEC project in collaboration with Latin America. In this paper a thorough examination of the general topic and the synthetic project's results are presented.

Adolescent↗
PubMed2005

Influence of the genetic polymorphism in the 5'-noncoding region of the CYP1A2 gene on CYP1A2 phenotype and urinary mutagenicity in smokers.

The functional significance of genetic polymorphisms on tobacco smoke-induced CYP1A2 activity was examined. The influence of three polymorphisms of the cytochrome P450 1A2 gene (CYP1A2) (-3860 G-->A (allele *1C), -2467 T-->delT (allele *1D), -163C-->A (allele *1F)), located in the 5'-noncoding promoter region of the gene, on CYP1A2 activity (measured as caffeine metabolic ratio, CMR), was studied in Caucasian current smokers (n=95). Tobacco smoke intake was calculated from the number of cigarettes/day. Also, studied was the influence of these CYP1A2 genotypes on smoking-associated urinary mutagenicity, detected in Salmonella typhimurium strain YG1024 with S9 mix, considering the urinary excretion of nicotine plus its metabolites as an internal indicator of tobacco smoke exposure. Smokers with at least one of the variant alleles CYP1A2 -3860A and -2467 delT showed a significantly increased CYP1A2 CMR (-3860 G/A versus G/G, p<0.05; -2467 delT/delT versus T/delT and T/T, p<0.01). Multiple regression analysis showed that the increase in CYP1A2 CMR (ln values) was again significantly related to the presence of CYP1A2 variants -2467delT and also to variant -163A (p<0.05), but moderately to -3860A (p=0.084). No influence of the number of cigarettes smoked per day by each subject was found. Heavy smokers (n=48, with urinary nicotine plus its metabolites>or=0.69 mg/mmol creatinine) with variant allele -2467delT or -163A had significantly increased urinary mutagenicity (p<0.01 and <0.05). CYP1A2 genetic polymorphisms are shown to influence the CYP1A2 phenotype in smokers, -2467 T-->delT having the main effect. This information is of interest for future studies assessing the possible role of tobacco smoke-inducible CYP1A2 genotypes as individual susceptibility factors in exposure to carcinogens.

Adolescent↗
PubMed2005

Obesity and genetic polymorphism of ERCC2 and ERCC4 as modifiers of risk of breast cancer.

To evaluate the relationship of genetic polymorphisms of ERCC2 and ERCC4 genes, both involved in nucleotide excision repair (NER), and the risk of breast cancer, a hospital-based case-control study was conducted in Korea. Histologically confirmed breast cancer cases (n = 574) and controls (n = 502) with no present or previous history of cancer were recruited from three teaching hospitals in Seoul during 1995-2001. Information on selected characteristics was collected by interviewed questionnaire. ERCC2 Asp(312)Asn (G>A) was genotyped by single-base extension assay and ERCC4 Ser(835)Ser (T>C) by dynamic allele-specific hybridization system. Although no significant association was observed between the genetic polymorphisms and the risk of breast cancer, women with both ERCC2 A allele- and ERCC4 C allele-containing genotypes showed a 2.6-fold risk (95% CI: 1.02-6.48) of breast cancer compared to women concurrently carrying the ERCC2 GG and ERCC4 TT genotypes. The breast cancer risk increased as the number of "at risk" genotypes increased with a borderline significance (P for trend = 0.07). Interactive effect was also observed between ERCC4 genotype and body mass idnex (BMI) for the breast cancer risk; the ERCC4 C allele containing genotypes posed a 1.7-fold (95% CI: 0.96-2.93) breast cancer risk in obese women (BMI>25 kg/m(2)) with a borderline significance. Our finding suggests that the combined effect of ERCC2 Asp(312)Asn and ERCC4 Ser(835)Ser genotypes might be associated with breast cancer risk in Korean women.

Breast Neoplasms↗
PubMed2004

Common genetic polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans.

AIMS/HYPOTHESIS: Resistin is thought to be an important link between obesity and insulin resistance. It has been suggested that genetic polymorphism in the promoter of resistin gene is a determinant of resistin mRNA expression and possibly associated with obesity and insulin resistance. In this study, we investigated the association between the genotype of resistin promoter and its plasma concentrations. METHODS: We examined g.-537A>C and g.-420C>G polymorphisms in the resistin promoter and measured plasma resistin concentrations in Korean subjects with or without Type 2 diabetes. We also did haplotype-based promoter activity assays and the gel electrophoretic mobility shift assay. RESULTS: The -420G and the -537A alleles, which were in linkage disequilibrium, were associated with higher plasma resistin concentrations. Individuals with haplotype A-G (-537A and -420G) had significantly higher plasma resistin concentrations than the others. Haplotype A-G had modestly increased promoter activity compared to the other haplotypes. Electrophoretic mobility shift assay showed that the -420G allele is specific for binding of nuclear proteins from adipocytes and monocytes. However, none of the two polymorphisms were associated with Type 2 diabetes or obesity in our study subjects. CONCLUSIONS/INTERPRETATION: Polymorphisms in the promoter of resistin gene are major determinants of plasma resistin concentrations in humans.

Aged↗
PubMed1998

[Genetic polymorphism of FXIII B subunit in seven Chinese populations].

OBJECTIVE: To understand the distribution of allele frequencies of blood factor XIIIB subunit(FXIIIB) in Chinese populations and evaluate the genetic polymorphism of FXIIIB for the purposes of population genetics and forensic haemogenetics. METHODS: The genetic polymorphism of FXIIIB subunit in seven Chinese populations was investigated. Isoelectrofocusing technique on polyoacrylamid gels followed by immunoblotting was used to determine the phenotype of individuals in each population sample. RESULTS: There were three common alleles in all the seven Chinese populations. The frequency of FXIIIB*3 was the highest, that of FXIIIB*2 was the lowest, and the one of FXXIIIB*1 was at the middle. All of them reached to the polymorphism's level. A rare variant allele was also found in some Chinese populations. Comparison of the constituents of FXIIIB phenotypes in the seven populations showed that there was no significant difference (P>0.05). The distribution of the allele frequencies in these populations reflected most likely the mode of the distribution in all Chinese populations. The phylogenetic tree and genetic distance, based on the allele frequencies of FXIIIB differentiated the populations in the world into the main ethnic groups as what other authors reported. CONCLUSION: FXIIIB is a useful genetic marker for population genetics and forensic haemogenetics.

China↗
PubMed2006

Interactive effect of genetic polymorphism of glutathione S-transferase M1 and smoking on squamous cell lung cancer risk in Korea.

To evaluate the role of the genetic polymorphisms of CYP2E1, GSTM1 and GSTT1, and their interaction with smoking in lung cancer development in Korean males, a hospital-based case-control study was conducted. Histologically confirmed male lung cancer patients (n=171) and male patients with no present or previous history of systemic illness who visited the urology department (n=196) were recruited from Seoul National University Hospital, Korea (1998-1999). CYP2E1 genotypes were determined by PCR-RFLP using RsaI digestion and GSTM1 and T1 genotypes were determined by multiplex PCR. Risks were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using a logistic regression model adjusting for age and pack-year. Smoking was a significant risk factor for lung cancer (P<0.001). Although genetic polymorphisms of CYP2E1, GSTM1 and T1 were not associated with the overall risk of lung cancer, the GSTM1 null genotype significantly increased the risk of squamous cell lung cancer (OR=1.9, 95% CI=1.04-3.60). An interactive effect between the GSTM1 null genotype and smoking was observed (P=0.04). These results suggest that the GSTM1 null genotype is associated with squamous cell lung cancer and modifies the effect of smoking on squamous cell lung cancer development in Korean males.

Adult↗
PubMed2001

Genetic polymorphisms and functional characterization of the 5'-flanking region of the human CYP2C9 gene: in vitro and in vivo studies.

OBJECTIVE: Genetic polymorphisms were identified in the 5'-flanking region of the human CYP2C9 gene, and their effects on the phenotype were evaluated on the basis of the luciferase reporter gene assay and the in vivo pharmacokinetics of phenytoin. METHODS: Genetic polymorphisms were screened by polymerase chain reaction-single-strand conformational polymorphism analysis, following sequencing with DNA samples obtained from 50 healthy volunteers and 133 adult epileptic patients. HepG2 hepatoma cells were cotransfected with various sequence patterns of 5'-flanking region-luciferase reporter gene constructs. Pharmacokinetic parameters of phenytoin in relation to the corresponding sequence patterns were estimated by the Bayesian method, and the results were compared with in vitro activities. RESULTS: Genetic analysis revealed the existence of 7 single nucleotide polymorphisms (SNPs). Allele frequencies of T-->C transition at position -1912 (T-1912C), C-1886G, C-1566T, G-1538A, C-1189T, G-982A, and A-162G were 0.019, 0.019, 0.077, 0.019, 0.579, 0.019, and 0.003, respectively. Some mutations occurred simultaneously, and a total of 6 sequence patterns (patterns 1-6) were observed. The luciferase reporter gene assay indicated that the presence of mutation(s) resulted in a reduction in luciferase activity of 41.4% (pattern 2) to 86.8% (pattern 5) compared with the activity of the wild-type construct. The calculated intrinsic clearance of phenytoin was also lower (up to a 40% reduction for pattern 2) when a mutation(s) was present. CONCLUSION: In addition to the two major mutations in the coding region (CYP2C9*2 and CYP2C9*3 ), mutations in the 5'-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity.

Adult↗
PubMed2005

[Genetic polymorphisms of NQO1, GSTT1, GSTM1 and susceptibility to chronic benzene poisoning].

OBJECTIVE: To explore the relationship between genetic polymorphism of quinone oxidoreductase 1 (NQO1), glutathione S-transferase theta 1 (GSTT1), glutathiones S-transferase mu 1 (GSTM1) and susceptibility to chronic benzene poisoning (BP). METHODS: The genotypes of NQO1, GSTT1, GSTM1 for 100 patients with benzene poisoning and 90 workers exposed to benzene who were engaged in the same working time and job title as patients with benzene poisoning were detected by PCR-RFLP and multi-PCR. RESULTS: There was a 2.82-fold (95% CI: 1.42 approximately 5.58, P < 0.05) increased risk of BP in the subjects with NQO1 C609T mutation genotype (T/T) compared with those carrying heterozygous (C/T) and wild type (C/C), and there was a 2.94-fold (95% CI: 1.25 approximately 6.90, P < 0.05) increased risk of BP in the subjects with NQO1 C609T T/T genotype compared with those carrying C/C genotype. The subjects with GSTT1 null genotype had a 1.91-fold (95% CI: 1.05 approximately 3.45, P < 0.05) increased risk of BP compared with those with GSTT1 non-null genotype. The interaction of two genes showed that there was a increased risk of BP in subjects with any two genotypes of NQO1 C609T T/T genotype and GSTT1 null genotype and GSTM1 null genotype, compared to the individual with any two genotypes of NQO1 C609T C/C genotype and GSTT1 non-null genotype and GSTM1 non-null genotype. The interaction of three genes showed that there was a 20.41-fold (95% CI: 3.79 approximately 111.11, P < 0.01) increased risk of BP in subjects with NQO1 C609T T/T genotype and GSTT1 null genotype and GSTM1 null genotype compared with those carrying NQO1 C609T C/T genotype and C/C genotype and GSTT1 non-null genotype and GSTM1 non-null genotype. CONCLUSIONS: The interaction of multi-genes may be an important role to BP. The genetic polymorphisms of 3 genes (NQO1, GSTT1 and GSTM1) led to declining of detoxifying ability in benzene metabolism, so the individual with NQO1 C609T T/T genotype, GSTT1 null genotype and GSTM1 null genotype is most susceptive to benzene. The results were consistent with that of the theoretic presumption. It could be suggested as a biomarker to assess the risk of benzene poisoning for individuals.

Adult↗
PubMed2000

Genetic polymorphism of thiopurine S-methyltransferase: molecular mechanisms and clinical importance.

The activity of thiopurine S-methyltransferase (TPMT) is inherited as an autosomal co-dominant trait. In most large world populations studied to date, approximately 10% of the population have intermediate activity due to heterozygosity at the TPMT locus, and about 0.33% is TPMT deficient. TPMT is now one of the most well characterized genetic polymorphisms of drug metabolism, with the genetic basis having been well defined in most populations, providing molecular strategies for studying this genetic polymorphism in human and experimental models. Three mutant alleles, TPMT(*)2, TPMT(*)3A and TPMT(*)3C, account for the great majority of mutant alleles in all human populations studied to date. Significant ethnic differences occur in the frequencies of these mutant alleles. Progress in DNA analysis has made it practical to use genotyping techniques for the molecular diagnosis of TPMT deficiency and heterozygosity, thereby avoiding adverse effects that are more prevalent in TPMT-deficient and heterozygous patients prescribed thiopurine medications.

Animals↗
PubMed2006

Genetic polymorphisms of cytochrome P450 2B6 gene in Han Chinese.

Cytochrome P450 (CYP2B6) is an important enzyme that metabolizes more than eight compounds and about 3.0% of therapeutic drugs. The genetic polymorphisms of CYP2B6 have earlier been studied in Caucasian, Japanese and Korean, but the data are lacking for Han Chinese. The aim of this study was to investigate the frequencies of allelic variants of CYP2B6 in healthy Han Chinese and compare with those in other ethnic groups reported in the literature. Polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method was used to test the five common non-synonymous single nucleotide polymorphisms (SNPs) of CYP2B6 gene, namely, 64C>T, 516G>T, 777C>A, 785A>G and 1459C>T in unrelated healthy Han Chinese (n=193). The study demonstrated that the frequencies of 64C>T, 516G>T, 777C>A, 785A>G and 1459C>T SNPs in Han Chinese were 0.03, 0.21, 0, 0.28 and 0.003, respectively. The frequencies of all five SNPs tested in female were higher than those in male, but the statistical difference was insignificant (P>0.05). Compared to the data reported in the literature, the frequencies of common CYP2B6 allelic variants in Chinese are similar to those of other Asian populations including Japanese and Korean, but markedly different from those in Caucasians. These results indicate the presence of marked ethnic difference in CYP2B6 SNP frequencies between Chinese and Caucasian. Further studies are required to explore the impact of these SNPs of CYP2B6 gene on the clinical response (efficacy and toxicity) to drugs that are substrates for CYP2B6 in patients.

Adult↗