Influence of CYP3A4, CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients

Objectives

Tacrolimus is a widely used immunosuppressive drug in organ transplantation. The oral bioavailability of tacrolimus varies greatly between individuals and depends largely on the activity of both the cytochrome P450 3A (CYP3A) subfamily and P-glycoprotein (P-gp). The possible influence of single nucleotide polymorphisms (SNPs) of CYP3A subfamily and P-gp (MDR-1) in liver transplant recipients has recently been indicated as one of the most important variables affecting the pharmacokinetics of tacrolimus and the renal injury induced by tacrolimus.

Methods

A total of 216 liver transplant recipients were enrolled in this study. The recipients' mean follow-up time was 52 mo (range from 16 to 96 mo). All liver transplant recipients were all in a stable stage with normal serum creatinine (SCr). All liver transplant recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), CYP3A4 intron 6 (CYP3A4*22), MDR-1 exon 26 (3435C>T) and exon 12 (1236 C>T) SNPs by HRM analysis (high-resolution melting curve analysis). Recipients were defined as the early renal injury by the elevation of different microproteins in the urine including microalbumin (MA), urine immunoglobulin G (IGU), urine transferrin (TRU) and α1-microglobulin (A1M).

Results

The daily dose of tacrolimus was higher for recipients with CYP3A5*1/*1 (AA) genotype than those with CYP3A5*3/*3 (GG) genotype [3.0 (2.0–4.0) versus 2.0 (1.5–2.5) mg/d, P < 0.05]. The concentration/dose ratio of recipients with CYP3A5*1 homozygotes was lowest compared to recipients with CYP3A5*3/*3 and CYP3A5*1/*3 genotypes. Furthermore, the recipients carrying CYP3A5*3 allele were associated with increased risk of early renal glomerular injury compared to the recipients carrying CYP3A5*1 allele (P = 0.01). MDR-1 polymorphisms were not related with tacrolimus pharmacokinetics and early renal injury.

Conclusion

CYP3A5 6986A>G genetic polymorphism affected daily dose requirements, concentration and nephrotoxicity of tacrolimus. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression outcome.     

Analysis of selected promoter polymorphisms and haplotypes of the CYBA gene encoding the p22phox,subunit of NADPH oxidases,in patients with coronary artery disease

Abstract

The p22phox is a critical component of vascular NADPH oxidases and is encoded by the CYBA gene. It was shown that functionally relevant polymorphisms of the CYBA gene ?930A?>?G, ?852C?>?G, ?675A?>?T, ?536C?>?T, 214C?>?T (previously described as 242C?>?T), *24A?>?G (previously described as 640A?>?G), and *49A?>?G modulate generation of reactive oxygen species (ROS). To analyse whether the CYBA gene polymorphisms ?852C?>?G, ?675A?>?T, and ?536C?>?T were associated with coronary artery disease (CAD), and to designate haplotype blocks. Four hundred and ninety subjects: 245 patients with CAD and 245 age and sex-matched controls. The polymorphisms were genotyped using the PCR-RFLP method and the TagMan^® Pre-designed SNP Genotyping Assay. The analysed polymorphisms do not form haplotype blocks. Case–control study revealed that the ?930?G/-675T and ?930G/*49G diplotypes were a CAD risk factor. The 675T/*49G diplotype can modulate CAD risk in women. The protective effect reducing CAD risk in women was related to the ?930A/?675T and ?930A/*49A diplotypes. Carrier state of the ?852C allele (?852C?>?G) was associated with multivessel stenosis while the CC genotype of the ?536C?>?T polymorphism was more frequent in patients with peripheral artery disease. Hypercholesterolemic, cigarette smokers had an increased risk of CAD, especially C???852 allele (?852C?>?G) carriers (SIM?=?3.54; odds ratios (OR)?=?10.01, p?<?0.000). The CYBA gene polymorphisms modulate the risk of CAD but do not form a haplotype blocks.     

Influence of CYP3A5, ABCB1 and NR1I2 polymorphisms on prednisolone pharmacokinetics in renal transplant recipients

The objective of this study was to evaluate whether genetic polymorphisms of CYP3A5 (A6986G, CYP3A5*3), ABCB1 (C1236T, G2677T/A, C3435T) and NR1I2 (A7635G) significantly impact the pharmacokinetics of prednisolone in renal transplant recipients. Ninety-five recipients were given repeated doses of triple therapy immunosuppression consisting of prednisolone, tacrolimus and mycophenolate mofetil. Twenty-eight days after renal transplantation, plasma prednisolone concentrations were measured by high-performance liquid chromatography. Comparisons of the CYP3A5 and ABCB1 genotypes revealed no significant differences in the prednisolone pharmacokinetics. The mean prednisolone C(max) for recipients (n=14) having both the ABCB1 3435CC genotype and the CYP3A5*3/*3 genotype was significantly higher than those (n=11) having both ABCB1 3435TT and CYP3A5*3/*3 genotypes (180ng/mL versus 129ng/mL, P=0.0392). The plasma concentrations of prednisolone in recipients having both ABCB1 3435CC and CYP3A5*3/*3 genotypes tended to be higher than those having both ABCB1 3435TT and CYP3A5*3/*3 genotypes. The mean AUC(0-24) and C(max) values for prednisolone in recipients having the NR1I2 7635G allele (AG: n=45, GG: n=32) were significantly lower than in patients having the 7635AA allele (n=18) (7635GG versus 7635AA, P=0.0308 for AUC(0-24), P=0.0382 for C(max) of prednisolone). In conclusion, NR1I2 (A7635G) rather than CYP3A5 or ABCB1 allelic variants affected patient variability of plasma prednisolone concentration. Recipients carrying the NR1I2 7635G allele seemed to possess higher metabolic activity for prednisolone in the intestine, greatly reducing its maximal plasma concentration.     

The prevalence of VKORC1 1639 G>A and CYP2C9*2*3 genotypes in patients that requiring anticoagulant therapy in Turkish population

The aim was to investigate the prevalence of VKORC1 and CYP2C9 genotypes in patients requiring anticoagulant therapy in two different region’s populations of Turkey. The recent cohort included 292 patients that needed anticoagulant therapy, and who had a history of deep vein thrombosis and/or pulmonary artery thromboembolism. Genomic DNA was isolated from peripheral blood samples and the StripAssay reverse hybridization or Real Time PCR technique was used for genotype analysis. Genotypes for CYP2C9 were detected as follows: 165 (56.5?%) for CYP2C9*1/*1, 67 (23.0?%) for CYP2C9*1/*2, 25 (8.6?%) for CYP2C9*1/*3, 9 (3.0?%) for CYP2C9*2/*2, 21 (7.2?%) for CYP2C9*2/*3, 5(1.7?%) for CYP2C9*3/*3 for CYP2C9 and the allele frequencies were: 0.723 for allele*1, 0.182 for allele*2 and 0.095 for allele*3 respectively. Genotypes for VKORC1 were detected as follows: 64 (21.9?%) for GG, 220 (75.4?%) for GA and 8 (2.7?%) for AA alleles. The G allele frequency was detected as 0.596, and the A allele frequency was 0.404. The VKORC1 1639 G>A and CYP2C9 mutation prevalence and allele frequency of the current results from two different populations (Sivas and Canakkale) showed similarly very variable profiles when compared to the other results from the Turkish population.     

Sex Differences in the Blood Concentration of Tacrolimus in Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients with <Emphasis Type="Italic">CYP3A5</Emphasis>*3/*3

The purpose of this study was to describe the impact of sex and cytochrome P450 3A5 (CYP3A5) variant on the blood concentration of tacrolimus in patients with systemic lupus erythematosus or rheumatoid arthritis. The blood concentration of tacrolimus (ng/mL) divided by the daily dose of tacrolimus (mg/day) and the patient’s weight (kg) (C/D) was obtained from 55 patients. The C/D value was analysed according to genetic variation in CYP3A5 or ATP binding cassette subfamily B member 1 (ABCB1), sex, and age. The C/D value in the CYP3A5*3/*3 group was significantly higher than in the CYP3A5*1/*1 and *1/*3 groups (p < 0.05, effect size: d = 1.40). In the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in men than in women (p < 0.05, effect size: d = 1.78). Furthermore, in the CYP3A5*3/*3 group, the concentration of tacrolimus was significantly higher in women aged over 50 years than in women aged under 50 years (p < 0.05, effect size: d = 1.18). In contrast, ABCB1 genetic variations did not show any significant effect on the C/D value. Since the blood concentration of tacrolimus in patients with CYP3A5*3/*3 varies depending on sex and age, these factors should be considered when studying the difference of sex in CYP3A.     

CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults.

A single-nucleotide polymorphism (A6986G) in the cytochrome p-450 3A5 (CYP3A5) gene distinguishes an expressor (*1) and a reduced-expressor (*3) allele and largely predicts CYP3A5 content in liver and intestine. CYP3A5 is the prevailing CYP3A isoform in kidney. We report that, among renal microsomes from 21 organ donors, those from *1/*3 individuals had at least eightfold higher mean kidney microsomal CYP3A5 content and 18-fold higher mean CYP3A catalytic activity than did those from *3/*3 individuals (P = 0.0001 and P = 0.0137, respectively). We also report significant associations between the A6986G polymorphism and systolic blood pressure (P = 0.0007), mean arterial pressure (P = 0.0075), and creatinine clearance (P = 0.0035) among 25 healthy African-American adults. These associations remained significant when sex, age, and body mass index were taken into account. The mean systolic blood pressure of homozygous CYP3A5 expressors (*1/*1) exceeded that of homozygous nonexpressors (*3/*3) by 19.3 mmHg. We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population.     

Personalized Tacrolimus Dose Requirement by CYP3A5 but Not ABCB1 or ACE Genotyping in Both Recipient and Donor after Pediatric Liver Transplantation

Tacrolimus (TAC) is the backbone of an immunosuppressive drug used in most solid organ transplant recipients. A single nucleotide polymorphism (SNP) at position 6986G>A in CYP3A5 has been notably involved in the pharmacokinetic variability of TAC. It is hypothesized that CYP3A5 genotyping in patients may provide a guideline for TAC therapeutic regimen. To further evaluate the impact of CYP3A5 variants in donors and recipients, ABCB1 and ACE SNPs in recipients on TAC disposition, clinical and laboratory data were retrospectively reviewed from 90 pediatric patients with liver transplantation and their corresponding donors after 1 year of transplantation. The recipients with CYP3A5 *1/*1 or *1/*3 required more time to achieve TAC therapeutic range during the induction phase, and needed more upward dose during the late induction and the maintained phases, with lower C/D ratio, compared with those with CYP3A5 *3/*3. And donor CYP3A5 genotypes were found to impact on TAC trough concentrations after liver transplantation. No association between ABCB1 or ACE genotypes and TAC disposition post-transplantation was found. These results strongly suggest that CYP3A5 genotyping both in recipient and donor, not ABCB1 or ACE is necessary for establishing a personalized TAC dosage regimen in pediatric liver transplant patients.     

Effects of the CYP3A4*1B Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis

Background and Objective

The association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients.

Methods

Studies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1.

Results

Seven studies (involving 1182 adult renal transplant recipients) were included in this meta-analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD -0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ -0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C₀/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post-transplantation.

Conclusion

Based on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian).     

Distribution of ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms in a Mexican Mestizos population

The aim of the present study was to establish the gene frequency of six polymorphisms of the ABCB1, CYP3A5, CYP2C19, and P2RY12 genes in a population resident of Mexico City. The proteins encoded by these genes have been associated with the absorption, and biotransformation of clopidogrel. The ABCB1 T3435C, CYP3A5 V3* A6986G, P2RY12 G52T, P2RY12 C34T, CYP2C19 V2* and V3* (positions G681A and G636A, respectively), polymorphisms were analyzed by 5′ exonuclease TaqMan genotyping assays in a group of 269 healthy unrelated Mexican Mestizo individuals. The CYP2C19 V3* G636A polymorphism was not detected in the Mexican Mestizos population. However, the studied population presented significant differences (P < 0.05) in the distribution of the T3435C, A6986G, G681A, G52T and C34T polymorphisms when compared to reported frequencies of Amerindian of South America, Caucasian, Asian, and African populations. In summary, the distribution of the ABCB1, CYP3A5, CYP2C19, and P2RY12 gene polymorphisms distinguishes to the Mexican Mestizos population from other ethnic groups.     

Pharmacogenetic-Based Efavirenz Dose Modification: Suggestions for an African Population and the Different CYP2B6 Genotypes

Background

Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.

Methods

In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.

Results

EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.

Conclusion

Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively.     

CYP2C19 Phenotype,Stent Thrombosis,Myocardial Infarction,and Mortality in Patients with Coronary Stent Placement in a Chinese Population

Background

Several studies have indicated that CYP2C19 loss-of-function polymorphisms have a higher risk of stent thrombosis (ST) after percutaneous coronary interventions (PCIs). However, this association has not been investigated thoroughly in a Chinese population. In this study, we aimed to determine the effect of CYP2C19*2 and CYP2C19*3 loss-of-function polymorphisms on the occurrence of ST and other adverse clinical events in a Chinese population.

Methods

We designed a cohort study among 1068 consecutive patients undergoing intracoronary stent implantation after preloading with 600 mg of clopidogrel. CYP2C19*2 and CYP2C19*3 were genotyped by using polymerase chain reaction-restriction fragment length polymorphism analysis. The adverse clinical events recorded were ST, death, myocardial infarction (MI), and bleeding events. The primary end point of the study was the incidence of cumulative ST within 1 year after PCI. The secondary end point was other adverse clinical outcomes 1 year after the procedure.

Results

The cumulative 1-year incidence of ST was 0.88% in patients with extensive metabolizers (EMs) (CYP2C19*1/*1 genotype), 4.67% in patients with intermediate metabolizers (IMs) (CYP2C19*1/*2 or *1/*3 genotype), and 10.0% in patients with poor metabolizers (PMs) (CYP2C19*2/*2, *2/*3, or *3/*3 genotype) (P<0.001). The one-year event-free survival was 97.8% in patients with EMs, 96.5% in patients with IMs, and 92.0% in patients with PMs (P = 0.014). Multivariate analysis confirmed the independent association of CYP2C19 loss-of-function allele carriage with ST (P = 0.009) and total mortality (P<0.05).

Conclusion

PM patients had an increased risk of ST, death, and MI after coronary stent placement in a Chinese population.     

CYP1B1 (4326C > G), CYP2F1 (c.14_15insC), CYP2J2 (?76G > T), and CYP2S1 (13106C > T and 13255A > G) polymorphisms and genetic predisposition to chronic respiratory diseases induced by smoking and occupational factors

The contribution of the polymorphic markers of cytochrome P450 genes to respiratory diseases caused by smoking and occupational factors has been assessed. For this purpose, PCR-RFLP analysis of the CYP1B1 (rs1056836, 4326C > G), CYP2F1 (rs11399890, c.14_15insC), CYP2J2 (rs890293, -76G > T), and CYP2S1 (rs34971233, 13106C > T and rs338583, 13255A > G) gene polymorphisms has been performed. The analysis has shown that CYP1B1 (rs1056836, 4326C > G) and CYP2F1 (rs11399890, c.14_15insC) polymorphisms may contribute to the development of occupational chronic bronchitis. The proportion of CYP1B1*1*3 heterozygotes in the group of patients with occupational chronic bronchitis is considerably greater than in the group of healthy workers (69.16% versus 53.29%; χ² = 5.94, p = 0.02, p _cur = 0.04, OR = 1.97, the 95% CI is 1.13–3.42). Patients with occupational chronic bronchitis and healthy workers significantly differed from each other in the CYP2F1 genotypes frequency distribution (rs11399890, c.14_15insC) (χ² = 6.18, d.f. = 2, p = 0.05). CYP2F1 wild type/ins heterozygous genotype frequency is higher in healthy workers (36.08%) than in patients (22.22%) (χ² = 5.48, p = 0.02, p _cur = 0.04, OR = 0.51, the 95% CI is 0.28–0.90). No association has been found between the CYP2J2 (rs890293, −76G > T) or CYP2S1 (rs34971233, 13106C > T, and rs338583, 13255A > G) gene polymorphisms and respiratory diseases.     

Association of CYP3A5*3 polymorphism with development of acute leukemia

BACKGROUND:

CYP3A5 was observed to be an important genetic contributor to inter individual differences in CYP3A-dependent drug metabolism in acute leukemic patients. Loss of CYP3A5 expression was mainly conferred by a single nucleotide polymorphism at 6986A>G (CYP3A5*3). We investigated the association between CYP3A5*3 polymorphism and acute leukemia.

MATERIALS AND METHODS:

Two hundred and eighty nine acute leukemia cases comprising of 145 acute lymphocytic leukemia (ALL), 144 acute myeloid leukemia and 241 control samples were analyzed for CYP3A5*3 polymorphism using PCR-RFLP method. Statistical analysis was performed with SPSS version (15.0) to detect the association between CYP3A5*3 polymorphism and acute leukemia.

RESULTS:

The CYP3A5*3 polymorphism 3/3 genotype was significantly associated with acute leukemia development (χ²- 133.53; df-2, P 0.000). When the data was analyzed with respect to clinical variables, mean WBC, blast % and LDH levels were increased in both ALL and AML cases with 3/3 genotype. The epidemiological variables did not contribute to the genotype risk to develop either AML or ALL.

CONCLUSION:

The results suggest that the CYP3A5*3 polymorphism might confer the risk to develop ALL or AML emphasizing the significance of effective phase I detoxification in carcinogenesis. Association of the polymorphism with clinical variables indicate that the 3/3 genotype might also contribute to poorer survival of the patients.     

Benzo(a)pyrene diolepoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons: association with specific CYP1A1, GSTM1, GSTP1 and EHPX genotypes

We investigated whether the presence of (+)-anti-benzo(a)pyrene diolepoxide adducts to serum albumin (BPDE-SA) among workers exposed to benzo(a)pyrene (BaP) and unexposed reference controls was influenced by genetic polymorphisms of cytochrome P4501A1 (CYP1A1), microsomal epoxide hydrolase (EHPX), glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), all involved in BaP metabolism. Exposed workers had significantly higher levels of adducts (0.124 ± 0.02 fmol BPTmg^?1 SA, mean ± SE) and a higher proportion of detectable adducts (40.3%) than controls (0.051 ± 0.01 fmol BPT mg^?1 SA; 16.1%) (p = 0:014 and p = 0:012). Smoking increased adduct levels only in occupationally exposed workers with the GSTM1 deletion (GSTM1 null) (p = 0:034). Smokers from the exposed group had higher adduct levels when they were CYP1A1 *1/*1 wild-type rather than heterozygous and homozygous for the variant alleles (CYP1A1 *1/*2 plus *2/*2) (p = 0:01). The dependence of BPDE-SA adduct levels and frequency on the CYP1A1 *1/*1 genotype was most pronounced in GSTM1-deficient smokers. Exposed workers with GSTM1 null/GSTP1 variant alleles had fewer detectable adducts than those with the GSTM1 null/GSTP1*A wild-type allele, supporting for the first time the recent in vitro finding that GSTP1 variants may be more effective in the detoxification of BPDE than the wild-type allele. Logistic regression analysis indicated that occupational exposure, wild-type CYP1A1*1/*1 allele and the combination of GSTM1 null genotype+EHPX genotypes associated with predicted low enzyme activity were significant predictors of BPDE-SA adducts. Though our findings should be viewed with caution because of the relatively limited size of the population analysed, the interaction between these polymorphic enzymes and BPDE-SA adducts seems to be specific for high exposure and might have an impact on the quantitative risk estimates for exposure to polycyclic aromatic hydrocarbons.     

Effect of cytochrome P450 3A5*3 genotype on the stereoselective pharmacokinetics of amlodipine in healthy subjects

Amlodipine is a racemic mixture composed of S- and R-form and metabolized stereoselectively. Cytochrome P450 3A (CYP3A) including CYP3A5 are involved in the metabolism of amlodipine and it was reported that polymorphic CYP3A5 genotype modulates the plasma levels of amlodipine and thus affect its pharmacokinetics. This study was conducted to find whether stereoselective pharmacokinetics of amlodipine was affected by the polymorphic CYP3A5 genotype. Seventeen healthy subjects were genotyped for CYP3A5*3 variant. After a single dose of 10-mg amlodipine, enantiomers of amlodipine were analyzed using HPLC-MS/MS equipped with an AGP column. Amlodipine showed stereoselective pharmacokinetics. S-amlodipine exhibited higher plasma levels than R-amlodipine in both genotype groups. S-amlodipine showed 15% higher mean peak plasma concentrations (Cmax) in CYP3A5*1/*3 carriers (3.28 ng/ml) than CYP3A5*3/*3 carriers (2.85 ng/ml) (P = 0.194) and R-amlodipine also showed 21% higher Cmax in CYP3A5*1/*3 carriers (3.33 ng/ml) than CYP3A5*3/*3 carriers (2.75 ng/ml) (P = 0.114). CYP3A5*1/*3 carriers also have 23 and 12% higher mean area under the time versus concentration curve of R-amlodipine and S-amlodipine than CYP3A5*3/*3 carriers, respectively (for R-amlodipine, 147.1 ng*h/ml for CYP3A5*1/*3 carriers versus 121.8 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.234; for S-amlodipine, 161.6 ng*h/ml for CYP3A5*1/*3 carriers vs. 144.2 ng*h/ml for CYP3A5*3/*3 carriers, P = 0.353). Other pharmacokinetic parameters also showed no significant difference between them. In conclusion, the present study showed that despite the evidence that amlodipine is stereoselectively metabolized, CYP3A5*3 genotype did not affect stereoselective disposition of amlodipine. It provides the evidence that CYP3A5*3genotype plays a minor role in the interindividual variability of stereoselective disposition of amlodipine in humans.     

Genetic polymorphisms of XRCC1 gene and susceptibility to gastric cancer in Chinese Han population

Abstract

This study aims to evaluate whether the c.1471G?>?A and c.1686C?>?G genetic polymorphisms of XRCC1 gene influencing gastric cancer susceptibility. A total of 813 subjects with Chinese Han ethnicity were enrolled. Our data suggest that the allele and genotype frequencies are significantly different from gastric cancer patients with cancer-free controls. We find that c.1471G?>?A and c.1686C?>?G genetic polymorphisms statistically increase the risk of gastric cancer. Our findings indicate these two genetic polymorphisms are related with the susceptibility to gastric cancer, and could be used as molecular markers for detecting gastric cancer in Chinese Han ethnicity.     

Assessment of clinical outcomes in breast cancer patients treated with taxanes: multi-analytical approach

Polymorphisms in genes encoding CYPs (Phase I) and ABCB1 (Phase III) enzymes may attribute to variability of efficacy of taxanes. The present study aims to find the influence of CYP and ABCB1 gene polymorphisms on taxanes based clinical outcomes. 132 breast cancer patients treated with taxanes based chemotherapy were genotyped for CYP3A4*1B, CYP3A5*3, CYP1B1*3, CYP2C8*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms using PCR-RFLP. Associations of genetic variants with clinical outcomes in terms of response in 58 patients receiving neo-adjuvant chemotherapy (NACT), and chemo-toxicity in 132 patients were studied. Multifactor dimensionality reduction (MDR) analysis was performed to evaluate higher order gene–gene interactions with clinical outcomes. Pathological response to taxane based NACT was associated with GA genotype as well as A allele of CYP3A5*3 polymorphism (P_corr = 0.0465, P_corr = 0.0465). Similarly, association was found in dominant model of CYP3A5*3 polymorphism with responders (P_corr = 0.0465). Haplotype analysis further revealed A_CYP3A4–A_CYP3A5 haplotype to be significantly associated with responders (P_corr = 0.048). In assessing toxicity, significant association of variant (TT) genotype and T allele of ABCB1 2677G>T/A polymorphism, was found with ‘grade 1 or no leucopenia’ (P_corr = 0.0465, P_corr = 0.048). On evaluating higher order gene–gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2–4 anemia and dose delay/reduction due to neutropenia (P = 0.024, P = 0.004, P = 0.026), respectively. Multi-analytical approaches may provide a better assessment of pharmacogenetic based treatment outcomes in breast cancer patients treated with taxanes.     

Clinically relevant pharmacogenetic markers in Tatars and Balkars

Molecular Biology Reports - This study was aimed to investigate the prevalence of CYP2C9*2 (p.430C?&gt;?T, rs1799853), CYP2C9*3 (p.1075A?&gt;?C, rs1057910), CYP4F2*3...     

The association of polymorphisms on TGFBR1 and colorectal cancer risk: a meta-analysis

Epidemiological studies found inconsistent results on the association of two variants on TGFBR1 (TGFBR1*6A and Int7G24A) with colorectal cancer (CRC) risk. The present study was aimed to evaluate the association of these two variants with CRC susceptibility via the meta-analysis methods. For variant TGFBR1*6A, nine reports including 6,765 CRC patients and 8,496 unrelated controls were identified. The heterozygotes *6A/*9A showed a significant increased risk of CRC with the pooled OR was 1.12 (95% CI = 1.02–1.23), and the pooled OR for the homozygotes *6A/*6A was 1.13 (95% CI = 0.80–1.58) compared to the homozygotes *9A/*9A. However, under the dominant effect model, the TGFBR1*6A carriers showed a significantly increased CRC risk (pooled OR = 1.12, 95% CI = 1.03–1.23, *6A/*6A and *6A/*9A vs. *9A/*9A). For variant Int7G24A, three case–control studies with 1,074 cases and 1,945 controls were found. Although no significant association was found for heterozygosity Int7G24A carriers with CRC risk (pooled OR = 0.97, 95% CI = 0.67–1.42), the homozygosity A/A carriers showed a significant elevated risk of CRC (pooled OR = 1.68, 95% CI = 1.14–2.47) compared to G/G homozygotes. Under the recessive effect model, homozygotes A/A showed a 71% increase of CRC risk compared to the A/G and G/G genotype carriers (pooled OR = 1.71, 95% CI = 1.17–2.51). These data strongly suggested that the two polymorphisms of TGFBR1 may confer low-penetrance susceptibility of CRC risk.     

The frequency and distribution of thiopurine S-methyltransferase alleles in south Iranian population

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathiopurine. Variability in TPMT activity is mainly due to genetic polymorphism. The frequency of the four allelic variants of the TPMT gene, TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G) were determined in an Iranian population from south of Iran (n = 500), using polymerase chain reaction (PCR)-RFLP and allele-specific PCR-based assays. Four hundred seventy four persons (94.8%) were homozygous for the wild type allele (TPMT*1/*1) and twenty five people were TPMT*1/*3C (5%). One patient was found to be heterozygous in terms TPMT*1 and *2 alleles with genotype of TPMT*1/*2 (0.2%). None of the participants had both defective alleles. The TPMT*3C and *2 were the only variant alleles observed in this population. The total frequency of variant alleles was 2.6% and the wild type allele frequency was 97.4%. The TPMT*3B and *3A alleles were not detected. Distributions of TPMT genotype and allele frequency in Iranian populations are different from the genetic profile found among Caucasian or Asian populations. Our findings also revealed inter-ethnic differences in TPMT frequencies between different parts of Iran. This view may help clinicians to choose an appropriate strategy for thiopurine drugs and reduce adverse drug reactions such as bone marrow suppression.