Cytochrome P450 2D6 Gene Polymorphisms Research Articles

Diltiazem efficacy and CYP2D6 gene polymorphism in patients with atrial fibrillation with rapid ventricular response

BackgroundDiltiazem stands out as one of the front-line drugs administered in the emergency department to achieve acute rate control in patients suffering from atrial fibrillation with rapid Ventricular Response. One of the cytochrome enzymes involved in the metabolism of diltiazem is cytochrome P450 2D6 (CYP2D6). Interindividual differences can act on drug metabolism and thus drug efficacy due to the genetic polymorphism induced by the CYP2D6 enzyme. This study explores the association between the efficacy of diltiazem and the genetic polymorphism of CYP2D6 in patients with atrial fibrillation with rapid ventricular response.Results87 out of 93 individuals with ventricular rate > 120 beats/min constituted the patient cohort. The patients were administered 0.25 mg/kg diltiazem intravenously. As a second dose, 0.35 mg/kg diltiazem was administered to patients who reportedly did not receive adequate drug efficacy. Heart rate control was considered to be achieved in patients whose heart rate fell below 110 beats/min and did not rise above 110 beats/min for 2 h. CYP2D6 *2, *3, *4 and *10 represent allele variants and *1 represents wild type (wt) allele. Achieving rate control after one or two doses of diltiazem in normal allele (wt/wt) carriers proved significantly higher than wt/*2, wt/*4 and wt/*10 heterozygous variant carriers. No significant difference was noted in wt/*3 heterozygous variant carriers.ConclusionThe presence of *2, *4 and *10 alleles was observed to significantly compromise the drug efficacy. *3 allele was found to bear no relation to the effect of diltiazem on achieving rate control.

Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with long term tramadol treatment-induced oxidative damage and hepatotoxicity

Our objective was to figure out whether CYP2D6 gene polymorphisms may account for long term tramadol-induced oxidative stress and hepatotoxicity in 60 patients receiving chronic tramadol treatment in Neurology and Rheumatology Outpatients Clinic, Zagazig University Hospitals, Egypt. As expected, CYP2D6*1 allele (wild type) frequency was significantly greater than CYP2D6*DUP, CYP2D6*4 and CYP2D6*10 alleles in both chronically tramadol-treated and control groups. In tramadol-treated patients, CYP2D6*DUP allele carriers followed by those carrying CYP2D6*1, displayed higher levels of urinary tramadol major active metabolite, O-desmethyltramadol (M1) and serum lipid peroxidation along with lower levels of total antioxidants than those carrying other impaired function alleles (CYP2D6*4&*10), suggesting oxidative stress. There were also significant increases in serum hepatic damage markers including alpha-glutathione transferase (α-GST) levels and liver function enzyme activities in *DUP and *1 carriers compared to carriers of other alleles. Moreover, we reported that in 42 patients with allele *1, tramadol caused mild to moderate hepatotoxicity (grades: 1–2) within 13–16 months while in 7 patients with duplicated allele (*DUP), tramadol caused moderate to severe hepatotoxicity (grades: 2–3) within 10–11 months (moderately longer period but shorter than that observed in allele *1), implying that exposure to tramadol for longer time in extensive and ultra-rapid metabolizers may contribute to hepatotoxicity development. Overall, our results suggest that CYP2D6 gene polymorphisms, particularly enhanced or normal function of CYP2D6, may increase the vulnerability to long term tramadol-induced hepatotoxicity through the enhancement of accumulation of tramadol bioactive metabolite (M1) and hence oxidative stress. Therefore, tramadol doses should be adjusted according to patient's CYP2D6 genotyping analysis to avoid hepatotoxicity.

CYP2D6 gene polymorphisms in Brazilian patients with breast cancer treated with adjuvant tamoxifen and its association with disease recurrence.

At present, there is controversy regarding the efficacy of tamoxifen in breast cancer patients who are carriers of cytochrome P450 2D6 (CYP2D6) gene polymorphisms, in terms of recurrence and overall survival. Thus, the aim of the present study was to investigate the association of the CYP2D6 *4, *10 and *17 gene polymorphisms with breast cancer recurrence in a Brazilian population. The cohort comprised 40 receptor-positive breast cancer patients without recurrence and 40 with distant recurrence. A 3-ml sample of peripheral blood was collected from each patient to determine the presence of the *4, *10 and *17 single nucleotide polymorphisms of the CYP2D6 gene by quantitative polymerase chain reaction analysis. There was no statistically significant difference between the two groups regarding the polymorphism frequency (P=0.246). The results revealed that intermediate metabolizers occurred in 5% of patients without recurrence and in 15% of those with distant recurrence. Poor metabolizers occurred in only 1 patient (2.5%) per group, and there was no significant difference between the groups (P=0.789). The present study concluded that the CYP2D6 gene polymorphism in women with hormone-sensitive breast cancer treated with tamoxifen was not associated with disease recurrence.

Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to β-blocker therapy in hypertension.

To investigate the associations between β1-adrenergic receptor (ADRB1) and cytochrome P450 2D6 (CYP2D6) gene polymorphisms and β-blocker treatment outcomes in patients with hypertension. Chinese patients with essential hypertension were treated with the β-blocker metoprolol and followed up for 12 weeks. xTAG® liquid-chip technology was used for CYP2D6 100 C > T and ADRB1 1165G > C genotyping. Associations between gene polymorphisms and antihypertensive therapy outcomes were assessed by generalized linear model fitting. A decrease of ≥ 10 mmHg in systolic blood pressure indicated an effective treatment outcome. A total of 93 patients were included in the study. Mutant allele frequencies of 61.29% and 58.60% were obtained for ADRB1 and CYP2D6, respectively. There was no significant interaction between the effects of ADRB1 and CYP2D6 gene polymorphisms on treatment outcome. Patients homozygous for the mutant ADRB1 genotype (CC) had better treatment outcomes than those heterozygous for the mutation (GC). Interestingly, β-blocker treatment duration was an independent factor associated with treatment outcome. The ADRB1 1165G > C gene polymorphism and β-blocker treatment duration are independent factors associated with β-blocker treatment outcome. These findings suggest that the selection of antihypertensive therapy should take into consideration the patient's genotype.

No association between cytochrome P450 2D6 gene polymorphism and risk of acute leukemia: evidence based on a meta-analysis

Background Many 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. Methods We 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. Results Overall, no significant association between CYP2D6*3 or *4 polymorphism and AL risk was found in this meta-analysis (+ 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. Conclusion CYP2D6*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.

Cytochrome P450 2D6 polymorphisms and predicted opioid metabolism in African American children with sickle cell disease.

The opioid medications codeine and hydrocodone, commonly prescribed in sickle cell disease (SCD), require metabolic conversion by cytochrome P450 2D6 (CYP2D6) to morphine and hydromorphone, respectively, to exert their analgesic effects. The CYP2D6 gene is highly polymorphic, with variant alleles that result in decreased, absent, or ultrarapid enzyme activity. Seventy-five children with SCD were tested for CYP2D6 polymorphisms, and metabolic phenotypes were inferred from the genotypes. The most common variant alleles were CYP2D6*2 (normal activity, 28.7%), CYP2D6*17 (reduced activity, 17.3%), CYP2D6*5 (gene deletion, 8.7%), and CYP2D6*4 (absent function, 8.0%). Normal/extensive metabolizer genotypes were found in 28/75 (37.5%), intermediate metabolism in 33/75 (44.0%), poor metabolism in 4/75 (5.3%), ultrarapid metabolism in 3/75 (4.0%), indeterminate in 6/75 (8.0%). Allele frequencies did not vary significantly among different hemoglobin genotypes. Identification of variant CYP2D6 genotypes may identify individuals with altered metabolism and therefore altered analgesic response to codeine and hydrocodone, thus providing a personalized medicine approach to treatment of pain in SCD. Further pharmacokinetic and pharmacodynamic studies are needed to define the relationship of CYP2D6 and other gene polymorphisms to individual opioid effect in SCD.

CYP1A2, CYP2D6, GSTM1, GSTP1, and GSTT1 gene polymorphisms in patients with bladder cancer in a Turkish population

Genetic differences in the metabolism of xenobiotics have recently been suggested as modifiers of individual susceptibility to bladder cancer (BC). The objective of this study was to investigate the relationship between bladder tumor and variants of cytochrome p450 1A2 (CYP1A2) 734 C --> A, cytochrome p450 2D6 (CYP2D6) 1934 G --> A, glutathione S-transferase M1, (GSTM1 null), glutathione S-transferase T1 (GSTT1 null), and glutathione S-transferase P1 (GSTP1) I105 V. We investigated the distribution of these polymorphisms in 135 BC patients and in 128 age and sex-matched cancer-free controls. The polymorphisms were analyzed using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay and the multiplex PCR method. Genotype and allele frequencies and their associations with BC risk, demographic factors, smoking status, and tumor stage were investigated. The prevalence of GSTT1 null genotype in cases was 23%, compared with 7% in the control group (OR = 3.94, 95% CI = 1.70-9.38, P = 0.001). There was no association between the studied polymorphisms of CYP1A2, CYP2D6, GSTM1, and GSTP1 genes and BC. There was an association between smoking status and BC. These data seem to indicate that GSTT1 gene polymorphism may be associated with BC in the Turkish population studied. Further studies will be needed to clarify the role of such variation in determining susceptibility to BC.

Polymorphisms of catechol- 0-methyltransferase (COMT), monoamine oxidase B (MAOB), N-acetyltransferase 2 (NAT2) and cytochrome P450 2D6 (CYP2D6) gene in patients with early onset of Parkinson ’s disease

The aim of the present study was to evaluate the contribution of MAOB, COMT, NAT2 and CYP2D6 gene polymorphisms to early onset Parkinson's disease (PD). The study enrolled 134 patients with Parkinson's disease (early onset—EOPD—67 patients, and late onset—LOPD—patients), and 66 healthy individuals. Polymerane chain reaction restriction fragment length polymorphism (PCR–RFLP) methods were used for genotyping. Univariate analysis revealed a significant two-fold higher EOPD risk among carriers of MAOB allele A or AA genotype. Multivariate analysis revealed that MAOB allele A was an independent factor predisposing to EOPD. It was shown that neither NAT2, CYP2D6 nor COMT genotype was associated with PD.

Cytochrome P450 2D6 polymorphism and character traits.

It has been suggested that cytochrome P450 2D6 (CYP2D6) is involved in dopamine metabolism within the brain. The dopamine system is suggested to play a role in determining normal character. The purpose of this study was to examine whether character traits are dependent on cytochrome P450 2D6 activity. We investigated the association between temperament and CYP2D6 gene polymorphism. The subjects were all Japanese and the polymorphism genotyped in the present study was CYP2D6*10. Character traits were assessed using the Temperament and Character Inventory. There was no overall or specific association between personality traits and the CYP2D6*10 allele and genotype frequencies. The present results do not support the hypothesis that CYP2D6 activity affects temperament and character.

Gene polymorphisms in detoxification enzymes as susceptibility factor for head and neck cancer?

Impaired detoxification of carcinogens found in tobacco smoke appears to increase the risk for tobacco associated cancer. The objective of this study was to investigate concomitant polymorphisms in genes encoding for various detoxification enzymes in patients with head and neck squamous cell carcinoma (HNSCC). In 187 patients with HNSCC and in 139 healthy control subjects, the polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), and glutathione S-transferase mu1 and Theta (GSTM1, GSTT1) were detected by polymerase chain reaction. No significant association were identified between CYP1A1 and CYP2D6 gene polymorphisms and HNSCC. Patients with laryngeal cancer revealed the GSTM1 null genotype more frequently than did the control subjects (P < 0.05). The coincidence of GSTM1 and GSTT1 null genotype was found twice as great in patients as in control subjects (P < 0.05). It is assumed that detoxification enzymes are functionally redundant and only the simultaneous deficiency of several detoxification enzymes increase the risk for HNSCC in alcohol- and tobacco-exposed individuals.

Gene polymorphisms in detoxification enzymes as susceptibility factor for head and neck cancer?

Impaired detoxification of carcinogens found in tobacco smoke appears to increase the risk for tobacco associated cancer. The objective of this study was to investigate concomitant polymorphisms in genes encoding for various detoxification enzymes in patients with head and neck squamous cell carcinoma (HNSCC). In 187 patients with HNSCC and in 139 healthy control subjects, the polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), and glutathione S-transferase mu1 and Theta (GSTM1, GSTT1) were detected by polymerase chain reaction. No significant association were identified between CYP1A1 and CYP2D6 gene polymorphisms and HNSCC. Patients with laryngeal cancer revealed the GSTM1 null genotype more frequently than did the control subjects (P < 0.05). The coincidence of GSTM1 and GSTT1 null genotype was found twice as great in patients as in control subjects (P < 0.05). It is assumed that detoxification enzymes are functionally redundant and only the simultaneous deficiency of several detoxification enzymes increase the risk for HNSCC in alcohol- and tobacco-exposed individuals.

Genetic association between cytochrome P-450 2D6 gene polymorphism and plasma concentration of haloperidol in Japanese schizophrenics.

Haloperidol is one of the major neuroleptics partly metabolized by cytochrome P-450 2D6 (CYP2D6), which has over 10 genetic polymorphisms. The purpose of this study was to investigate whether individual haloperidol plasma concentration was affected by CYP 2D6 gene polymorphisms. The genomic DNA of 56 subjects who have been taking haloperidol were analysed by restriction fragment length polymorphism (RFLP) method to detect the major Caucasian mutations, CYP 2D6A, 2D6B, and the major oriental population mutation, 2D6J. We found 10 cases of the CYP 2D6J mutation, only one case of the CYP 2D6B mutation, and no cases of the CYP 2D6A mutation in the present subjects. Contrary to expectations, haloperidol plasma concentration of the CYP 2D6B mutation case showed a lower haloperidol plasma concentration than the mean value of that of wild type homozygous cases. Haloperidol plasma concentration of 10 subjects who had the CYP 2D6J mutation cases showed no significant difference from that of the wild type homozygous group. These results suggest that the major genetic polymorphisms of CYP 2D6 do not seem to be one of the factors which affect individual haloperidol plasma concentration in Japanese schizophrenics.

Cytochrome P-450 2D6 gene polymorphism is not associated with neuroleptic malignant syndrome

Cytochrome P-450 2D6 gene polymorphism is not associated with neuroleptic malignant syndrome