CYP2B6 Polymorphisms Research Articles

The Effects of Cumulative Dose and Polymorphisms in CYP2B6 on the Mitotane Plasma Trough Concentrations in Chinese Patients With Advanced Adrenocortical Carcinoma.

Mitotane is the only drug approved to treat adrenocortical carcinoma (ACC), and a relationship of pharmacokinetic/pharmacodynamic has been characterized. However, limited evidence concerning affecting factors in large interindividual variability of the pharmacokinetics of mitotane is available. To address this question, a retrospective analysis was performed on ACC Chinese patients treated with mitotane for more than 3 months. Mitotane plasma trough concentrations were detected at the steady state, and CYP2B6, CYP3A4, and pregnane X receptor (PXR) polymorphisms were genotyped. After examining homogeneous pharmacologic data, we restricted the analyses to 36 patients that received mitotane for a median (interquartile range, IQR) of 9 months (5.00–22.50) with a median dose of 2 g/day (2.00–2.50). As a result, drug exposure was significantly influenced by the cumulative dose of mitotane, and CYP2B6 516GG and CYP2B6 26570CC were at high risk to be below the therapeutic range of mitotane. No association was found between mitotane concentrations with CYP3A4 or PXR polymorphism. Our data firstly indicated that the cumulative dose of mitotane and polymorphisms of CYP2B6 516 and CYP2B6 26570 might significantly affect mitotane plasma trough concentrations in Chinese ACC patients.

Influence of CYP2B6 and CYP3A4 polymorphisms on the virologic and immunologic responses of patients treated with efavirenz-containing regimen.

The main objective of this study was to evaluate the effect of CYP2B6 and CYP3A4 polymorphisms on the virological and immunologic responses of HIV patients. A total of 153 HIV-positive patients were enlisted for the study. Viral load and median CD4 T cell counts were evaluated at baseline and month 6 (M6). Samples were identified using TaqMan genotyping assays. The AG in CYP2B6 rs2279343 was associated with VLS compared to homozygous AA. In the dominant model, the AG/GG genotypes were associated with VLS compared to the AA genotype. Moreover, in overdominant model, the AG genotype was associated with VLS compared to AA/GG. Regarding immunological response, only the AG in SNP rs2279343 CYP2B6 was associated with an increase in CD4 cell count between baseline and M6. In CYP2B6 rs3745274, the CD4 cell count at M6 was higher than that of baseline for GG carriers and for GT carriers. In CYP3A4 rs2740574, the TC carriers showed a higher median CD4 count at M6 compared to that of the baseline count, as well as for CC carriers. The best genotypes combination associated with CD4 cell count improvement were AA/AG in SNP rs2279343 and GG/GT in SNP rs3745274. Our findings support the fact that CYP2B6 rs2279343 could help in the prediction of VLS and both SNPs rs3745274 and rs2279343 in CYP2B6 and CYP3A4 rs2740574 were associated with immune recovery in Malian HIV-positive patients.

Pharmacogenetic predictors of variability in efavirenz pharmacokinetics in an admixed Brazilian HIV cohort

To investigate the influence of pharmacogenetic polymorphisms on efavirenz (EFV) exposure and metabolism in HIV-infected Brazilians under treatment with EFV-containing antiretroviral (ART) regimens. HIV-positive adults (n =82) on stable ART regimens containing 600 mg EFV once daily for at least 6 months were recruited at 2 university hospitals. Blood samples collected at mid-dose interval were used to quantify the plasma concentrations of EFV (denoted [EFV]), its major metabolite 8-OH-EFV ([8-OH-EFV]) and [8-OH-EFV]/[EFV] metabolic ratio, and to genotype single nucleotide polymorphisms in CYP2B6 (rs3745274, c.516G > T; rs28399499, c.983 T > C) and ABCB1 (rs3842, c.4036G > A). CYP2B6 metabolic phenotypes were inferred from the CYP2B6 diplotypes. Linear regression modelling was applied to identify sociodemographic, clinical and pharmacogenetic predictors of [EFV] and [8-OH-EFV]/[EFV] metabolic ratio. Wide (50-fold) interindividual variation in [EFV], [8-OH-EFV] and [8-OH-EFV]/[EFV] was observed; 69.5% of participants had [EFV] within the nominal therapeutic range (1000-4000 ng/mL), while 19.5 and 11.0% had [EFV] below and above this range, respectively. Multiple regression modelling retained only CYP2B6 metabolic phenotypes or the combined rs3745274 and rs28399499 genotypes, as significant predictors of [EFV] and [8-OH-EFV]/[EFV]. EFV exposure and disposition varied widely among HIV-infected Brazilians under stable treatment with EFV-containing ART regimens. About 1/10 of the participants had [EFV] exceeding nominal supratherapeutic concentration (4000 ng/mL), but reported tolerance to the ARV regimens, while 1/5 of participants had nominal subtherapeutic [EFV] (<1000 ng/mL) but adequate virological response. Genotype for the 2 CYP2B6 single nucleotide polymorphisms studied explained 48% of variation in [EFV] and 35% of variation in [8-OH-EFV]/[EFV].

Effects of Efavirenz for the Treatment of HIV Section on the Basis of Genetic Polymorphisms

Introduction: CYP2B6 is a liver enzyme that is involved in the metabolism of several drugs including Efavirenz, which is one of the mainstay treatments for Acquired Immunodeficiency Syndrome (AIDS) caused by the Human Immunodeficiency Virus (HIV). Polymorphisms in the CYP2B6 gene determine the rate of enzyme activity. One such polymorphism, rs3745274, where there is a change from G to T at codon 516 results in an amino acid change from glutamine to histidine at position 172. The Food and Drug Administration (FDA) USA has recommended this molecular marker as a companion diagnostic test for Efavirenz. Aim: To evaluate the effect of Efavirenz in the treatment of HIV on the basis of genetic polymorphisms. To determine the CYP2B6 genotype of healthy individuals and those with HIV before starting the antiretroviral therapy. To review the reported cases of genetic polymorphisms and document drug toxicity in the selected population. Materials and Methods: A prospective clinical observational study was done at Kamineni Hospital, Hyderabad, Telangana, India, from September 2017 to August 2020 with an inclusion criterion of participants above the age of 18 years who are HIV positive diagnosed by Enzyme Linked Immunosorbent Assay (ELISA) test, reporting to the Outpatient Department (OPD) or getting admitted for treatment with Efavirenz with a sample size of 369 based on the prevalence of CYP2B6 polymorphism in Southern India. Results: Out of the study population, 276 HIV patients and 93 controls were genotyped by Polymerase Chain Reaction (PCR) and subjected to Restriction Fragment Length Polymorphism (RFLP) technique to establish CYP2B6 - 516 G&gt;T polymorphism. About 69% is of GT genotype, 18% is of TT genotype and 13% is of GG genotype. Patients with GT genotype are intermediate metabolisers of the drug, those with TT genotype are poor metabolisers of the drug, and GG genotype is an extensive metaboliser of the drug. Individuals with the 516T allele have low enzyme activity and are poor metabolisers of the drug, causing delayed clearance leading to Adverse Drug Reactions (ADR) causing neurological deficits and cardiac complications. Conclusion: This observation helps the clinician adjust the dose of Efavirenz by studying the genetic polymorphism of the patient. Based on this study, we recommend that all HIV diagnosed patients undergo CYP2B6 genotyping before starting an Efavirenz based regimen to decrease the adverse drug reactions and promote effective Highly Active Antiretroviral Therapy (HAART) therapy.

The Cyp2b6 Gene Polymorphism and Phenotypic Correlation of Efavirenz-Based Combination Therapy Among the Niger Delta Ethnic Population: Implications in Modern Pharmacogenomics.

PurposeDNA polymorphism describes the difference between individuals, groups, or ethnicities, races, etc., in terms of their DNA sequences or phenotypes as relates to drug metabolism. Using predictive genotyping of drug-metabolizing genes, we can develop individuals’ drug therapies that are less toxic and more effective. The main aim of the study was to evaluate genotype–phenotype-based correlation and incidence of genetic polymorphism of efavirenz blood levels among HIV/AIDS patients of the Niger Delta population.MethodsA study questionnaire was designed to obtained patients’ data, blood samples were obtained, plasma was separated from the serum using a centrifuge for 5 minutes at 4000 rpm for HPLC analysis, polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was conducted using Bsrl endonuclease enzyme to digest the PCR amplicons. Standard efavirenz was used at 0.5, 1, 2, 4, 16 mg/L to construct a calibration curve. Data were analyzed with SPSS software using chi-square test at p-value ≤0.5 and Microsoft excel 2013, while PCR and RFLP results were obtained after 1% Agarose gel electrophoresis, respectively.ResultsPhenotypic results showed that the participants had different efavirenz plasma concentrations. Six subjects (12%) had efavirenz plasma levels below 0.10 mg/L, considered ultra-rapid metabolizers (UMs), 22 (44%) 0.10 mg/L to 0.90 mg/L, classified as extensive metabolizers (EMs), 19 (38%) had 1.0 to 3.9 mg/L and were noted as intermediate metabolizers (IM), while 3 (6%) subjects showed efavirenz plasma levels from 4.0 mg/L to 6.0 mg/L, categorized as poor metabolizers (PM). RFLP results showed more than half of the population (56%) with a homozygous wild-type gene with CYP2B6*1*1 allele, 38% were CYP2B6*1*6 (heterozygous mutant) allele and 6% had homozygous mutant gene (CYP2B6*6*6 allele). Out of the 15 male subjects among the 50 patients that participated in the study, 8% were UM, 12% EM, 14% IM while no PM was observed, on the contrary, out of the 35 females participated in the study, 4% were observed as UM, 32% EM, 24% IM, while 6% were PM.ConclusionThere was no significant difference (p ≤ 0.05) between genotype and phenotype data for CYP2B6 polymorphism, among the HIV/AIDS patients that participated in this study. Genetic polymorphism of the CYP2B6 gene is prevalent among HIV/AIDs patients in the Niger Delta ethnic population on efavirenz-based HAART treatment, as the population having homozygous mutant gene or PM are >1% (6%).

Comprehensive Next-Generation Sequencing Reveals Novel Predictive Biomarkers of Recurrence and Thoracic Toxicity Risks After Chemoradiation Therapy in Limited Stage Small Cell Lung Cancer

Although definitive chemoradiation therapy (dCRT) remains the most effective treatment modality in limited stage small cell lung cancer (SCLC), some patients progress quickly or develop serious radiation-induced thoracic toxicity (RITT). Molecular correlates of response to dCRT remain to be explored.Genomic profiling was performed retrospectively on 231 patients with limited-stage SCLC treated with dCRT between 2015 and 2019 using a customized panel covering cancer and radiation therapy response-related genes. Exploratory associations of progression-free survival, overall survival, and RITT with clinical features, tumor genetics, genomic and molecular pathway alterations, and single nucleotide polymorphisms were conducted.In addition to the common SCLC genes, such as TP53, RB1, and NOTCH1/2, potentially actionable mutations in EGFR, KRAS, and BRCA1/2 were among the top alterations in the cohort. At the single-gene level, CDK4 and GATA6 alterations were independent predictors of poor survival by multivariate analysis. At the genomic level, high tumor mutational burden was strongly associated with favorable survival outcome. Pathway-level analysis showed that activating mutations in the MAPK/ERK pathway genes, particularly those in EGFR/ERBB2, correlated with poor survival. Combined analysis enabled optimized risk stratification of post-dCRT survival. On the other hand, our study also confirmed that single nucleotide polymorphisms in MTHFR, CYP2B6, NQO1, and LIG4 were risk alleles of high-grade RITT. Remarkably, somatic loss-of-function mutations in the DNA damage repair pathway genes were associated with increased risk of high-grade RITT, particularly pneumonitis, which likely reflect a complex interplay between the tumor and its immune microenvironment.Taken together, by examining the mutational landscape of a large cohort of limited-stage SCLC, we identified novel molecular predictors of survival and RITT. Our findings also implicate several key molecular pathways, including the MAPK/ERK and DNA damage repair pathways, in the regulation of dCRT response.

Effect of albumin and CYP2B6 polymorphisms on exposure of efavirenz: A population pharmacokinetic analysis in Chinese HIV-infected adults

BackgroundEfavirenz is a vital component used to treat HIV-1 infection. Nevertheless, it shows large between-subject variability, which affects both its therapeutic response and adverse effects. ObjectiveTo investigate the impact of gene polymorphisms and non-genetic factors on the variability of efavirenz pharmacokinetics and to propose the optimal dose regimens. MethodsA total of 769 plasma samples from 376 HIV-infected Han Chinese outpatients were collected to develop a population pharmacokinetic model using NONMEM software. The impact of patient demographics, laboratory tests, concomitant medication, and genetic polymorphisms of CYP2B6 and ABCB1 on efavirenz pharmacokinetics were explored. According to the final model, the model-informed dose optimization was conducted. ResultsThe pharmacokinetics of efavirenz was characterized by a one-compartment model with first-order absorption and elimination. The typical values of the estimated apparent oral clearance, volume of distribution, and absorption rate constant in the final model were 9.44 L/h, 200 L, and 0.727 h − 1, respectively. Efavirenz clearance was significantly influenced by CYP2B6 variants, including rs2099361, rs3745274, and rs2279343, along with albumin and weight. The volume of distribution was affected by albumin and weight. Based on the CYP2B6 polymorphisms of patients, the recommended daily doses of efavirenz were 100 mg for CYP2B6 slow metabolizers, 400 or 600 mg for intermediate metabolizers, and 800 or 1000 mg for extensive metabolizers. ConclusionsPolymorphisms of CYP2B6, along with albumin and weight, resulted as the predictors of efavirenz pharmacokinetic variability, which could be used in prescribing optimal efavirenz doses.

Busulfan Pharmacogenetics and Drug Exposure in Cancer Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction: Busulfan, a bifunctional alkylating agent widely used in conditioning regimens before hematopoietic stem cell transplantation (HSCT), is metabolized via glutathione-S-transferases (GSTs) and cytochrome P450 (CYP) enzymes. Busulfan demonstrates wide interpatient variability in pharmacokinetics (PK); high drug exposure is associated with increased risk of toxicities (e.g. veno-occlusive disease) and low drug exposure is associated with increased risk of relapse and graft failure. Drug exposure within a narrow therapeutic range yields optimal results. PK-guided dosing is used in many patients to achieve optimal drug exposure; however, better methods to select the initial dose would improve consistency of busulfan exposure and the likelihood of achieving the target area under the concentration-time curve (AUC). Previous pharmacogenomic (PGx) studies have identified GST polymorphisms as predictors of drug exposure, however, these were primarily performed in pediatric populations and/or Asians. We performed a PGx study in adult HSCT patients to identify polymorphisms in candidate genes associated with busulfan AUC and clearance.Methods: Buccal swabs were collected from HSCT patients scheduled to receive busulfan as part of their conditioning regimen on the day of admission (one day prior to initiating busulfan) between 04/28/14 and 06/06/2017. DNA was extracted using the GenElute™ Mammalian Genomic DNA Kit. A custom Ion AmpliSeq™ PGx Panel and various orthogonal methods were used to genotype the samples for polymorphisms in GSTA1 (135T>C), GSTM1 (null/present), GSTP1 (Ile105Val, Ala114Val), CYP2B6 (*2, *4, *5, *6, *18, *22), CYP2C8 (*2, *3), CYP2C9 (*2, *3, *8, *11), CYP2C19 (*2, *3, *17), and MTHFR (A1298C, C677T). Phenotypes were inferred according to established guidelines or literature. IV busulfan was administered once daily over 3 hours at 2.8 mg/kg (for autos) or 3.2 mg/kg (for allos) for a total of 4 doses. PK samples were obtained at 15 mins, 1 hr, 2 hrs, 3 hrs, and 5 hrs after the end of the first infusion. Non-compartmental analysis was performed to estimate PK parameters and doses 3 and 4 were adjusted to target an AUC of either 4500 or 5000 uM*min/L, depending on transplant type and conditioning regimen. The primary objective was to investigate the impact of polymorphisms on busulfan AUC, which was measured using univariate linear regression analysis adjusting for dose. Secondary objectives included a comparison of mean AUCs between phenotypes, which was measured using ANOVA, and to determine the association between SNPs and busulfan clearance using univariate linear regression adjusting for dose.Results: A total of 36 patients were evaluable for the primary endpoint. The median age was 47 (22-73) years, 56% were male, 75% received busulfan/cyclophosphamide/etoposide, 22% received busulfan/cyclophosphamide with post-transplant cyclophosphamide, and 3% received thiotepa/busulfan/cyclophosphamide. The genotype and inferred phenotype frequencies are summarized in Table 1. The mean AUC across all patients was 4255 µM*min/L (range 2834-5989). Results from the univariate linear regression analysis identified that CYP2B6 polymorphisms were significantly associated with busulfan AUC (intermediate [IM] vs. poor metabolizer [PM], p = 0.05; normal/rapid metabolizer [NM/RM] vs. PM, p = 0.02) (Table 2). The mean AUC in CYP2B6 PMs, IMs, NM/RMs was 5242, 4277, and 4134 µM*min/L, respectively (p = 0.03 by ANOVA test). There was no association of polymorphisms in GSTA1, GSTM1, GSTP1, CYP2C8, CYP2C9, CYP2C19 and MTHFR with AUC. CYP2B6 polymorphisms were also associated with busulfan clearance (IM vs. PM, p = 0.07; NM/RM vs. PM, p = 0.03).Conclusion: CYP2B6 polymorphisms were significantly associated with busulfan AUC and clearance; these appear to be an important determinant of drug exposure, however, GST polymorphisms did not replicate as significant, possibly due to differences in patient populations. PGx testing for CYP2B6 may provide an important tool to individualize up front dosing and improve the likelihood of achieving the target AUC earlier or to achieve target AUC in a higher proportion of the many patients who do not receive PK-guided dosing; however, our findings require further validation in larger cohorts of patients. We plan to enroll more patients and assess the relationship between PK, PGx and clinical outcomes, including toxicity and response. [Display omitted] DisclosuresTrivedi:Pharmacyclics: Consultancy, Honoraria. Grunwald:Pfizer: Consultancy; Alexion: Consultancy; Incyte: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; ARIAD: Consultancy; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Janssen: Research Funding. Ghosh:AbbVie: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jassen: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding.

Association of CYP27B1 Polymorphism and Vitamin D Levels with Multiple Sclerosis Development in Lebanese Population of Bekaa Region: A Preliminary Study

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Interaction between genetic and environmental factors guides the development of the disease. Among environmental factors, vitamin D deficiency is shown to increase the risk of MS development. Several single nucleotide polymorphisms (SNPs) in cytochrome P450 family 27 subfamily B (CYP27B1) gene that encodes the rate-limiting enzyme involved in vitamin D metabolism, were shown to be correlated with MS. We aimed at investigating the association of CYP27B1 gene polymorphisms and vitamin D level with MS development in a sample of Lebanese MS patients living in the Bekaa region. Enrolled MS patients and controls were age and gender matched. Genotyping was performed by sequencing the amplified CYP27B1 PCR products. Vitamin D levels were measured using a VIDAS® 25 OH Vitamin D total assay based on enzyme linked fluorescent assay (ELFA). Chi-square and Mann-Whitney U tests were used for statistical analysis. A significant association was shown between vitamin D deficiency and MS without any association between CYP27B1 studied SNPs and the disease. We confirmed that vitamin D deficiency was associated with MS with no implication of the studied SNPs of CYP27B1 gene with disease susceptibility among the Lebanese MS patients living in the Bekaa region.

Associations between efavirenz concentrations, pharmacogenetics and neurocognitive performance in people living with HIV in Nigeria.

Objective:Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance.Design:Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected.Methods:Participants (N = 93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography–tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning.Results:Strong correlation (r = 0.66, P < 0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85 ng/mg (4.56–10.93). CYP2B6 516G>T, (P < 0.001) and CYP2B6 983T>C (P = 0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (P < 0.001) and 983T>C (P = 0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (r = 0.23, P = 0.043) and 983T>C genotype (r = 0.38, P < 0.0005).Conclusion:This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.

Impact of Cytochromes P450 3A4 and 2B6 gene polymorphisms on predisposition and prognosis of acute myeloid leukemia: an Egyptian case-control study

BackgroundIt has been postulated that the interaction between environmental risk factors and genetic susceptibility is a possible cause for the development of acute myeloid leukemia (AML). Cytochrome P450 (CYP) detoxification enzymes are responsible for the elimination of oxidative stress. Genetic polymorphisms in these enzymes may cause AML due to enhanced accumulation of reactive oxygen species. To study the association between CYP3A4 (A290G) and CYP2B6 (G516T) gene polymorphisms and the predisposition and prognosis of AML, 50 upfront AML patients and 50 healthy individuals were genotyped for CYP2B6 (G516T) and CYP3A4 (A290G) single-nucleotide polymorphisms (SNPs) using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) technique. The polymorphisms were evaluated in relation to the response to chemotherapy and survival.ResultsCYP2B6 gene mutation carries a threefold risk of developing AML (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.3–6.9), whereas CYP3A4 gene mutation carries approximately fourfold risk (OR, 3.8; 95% CI, 1.4–10.1). The presence of combined gene mutation conferred about 15-fold increased risk of developing AML compared with the presence of a single gene mutation (OR, 14.8; 95% CI, 1.8–124.2). CYP3A4 gene mutation is associated with worse overall survival (P = 0.030).ConclusionCYP enzyme gene polymorphisms are associated with the development of AML. Elimination of oxidative stress in genetically susceptible individuals may decrease the risk of AML and may improve survival.

Sequence Polymorphism in Xenobiotic Metabolising Genes in Iraqi Colorectal Cancer Patients.

Objectives:Colorectal cancer (CRC) is the third most prevalent malignant neoplasm. Genetic variations in the xenobiotic metabolising cytochrome enzymes. Family 1 Subfamily A Member 1 (CYP1A1) and Family 1 Subfamily B Member 1 (CYP1B1) might play a role in cancer pathogenesis and prognosis. The aim of this work is to determine the frequency of Single Nucleotide Polymorphisms (SNPs) in CYP1A1 (rs1048943, Ile462VaI and rs4646903/MSP1) and CYP1B1 (rs1056836, Leu432Val) genes in patients with CRC cancer. It was also an attempt to identify the association between SNPs and CRC and its stage and grade at diagnosis. Methods:This case-control study was conducted in Kirkuk/Iraq, 200 patients with CRC and 200 cancer free control subjects were enrolled. Genomic DNA was extracted from venous blood samples and screened for SNPs using Restriction Fragment Length Polymorphism (RFLP) and confirmed by the direct DNA sequencing. Results:The reference genotype of CYP1A1 gene rs1048943 is AA. Both the AG and GG variants were significantly more frequent in the cancer group and associated with increased risks of CRC and its later stages (stages III and IV) and poor differentiation (p<0.01). The reference genotype of CYP1A1 rs4646903 is TT. The variant genotypes, TC and CC, had no significant association with increased odds of cancer (P>0.05) or with tumour stage or its grade (p>0.05). The GG genotype of CYP1B1 rs1056836 was the reference genotype. The CG and CC variants were not associated with increased risks of CRC (P>0.05) or its stage or grade except the CG genotype which was associated with poor differentiation (OR= 3.4, 95 % CI= 1.8 -6.5, P<0.001). Conclusion:CYP1A1 gene rs1048943 SNPs can represent a potential future marker for CRC risk prediction and prognosis. Further evaluation in large scale studies will provide greater understanding of the effects of other genes SNPs on CRC risk and prognosis.

PharmVar GeneFocus: CYP2B6.

The Pharmacogene Variation Consortium (PharmVar) catalogs star (*) allele nomenclature for the polymorphic human CYP2B6 gene. Genetic variation within the CYP2B6 gene locus impacts the metabolism or bioactivation of clinically important drugs. Of particular importance are efficacy and safety concerns regarding: efavirenz, which is used for the treatment of HIV type-1 infection; methadone, a mainstay in the treatment of opioid use disorder and as an analgesic; ketamine, used as an antidepressant and analgesic; and bupropion, which is prescribed to treat depression and for smoking cessation. This GeneFocus provides a comprehensive overview and summary of CYP2B6 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network.

The noradrenaline and dopamine reuptake inhibitor bupropion is metabolized by CYP2B6 and recommended by the FDA as the only sensitive substrate for clinical CYP2B6 drug–drug interaction (DDI) studies. The aim of this study was to build a whole-body physiologically based pharmacokinetic (PBPK) model of bupropion including its DDI-relevant metabolites, and to qualify the model using clinical drug–gene interaction (DGI) and DDI data. The model was built in PK-Sim® applying clinical data of 67 studies. It incorporates CYP2B6-mediated hydroxylation of bupropion, metabolism via CYP2C19 and 11β-HSD, as well as binding to pharmacological targets. The impact of CYP2B6 polymorphisms is described for normal, poor, intermediate, and rapid metabolizers, with various allele combinations of the genetic variants CYP2B6*1, *4, *5 and *6. DDI model performance was evaluated by prediction of clinical studies with rifampicin (CYP2B6 and CYP2C19 inducer), fluvoxamine (CYP2C19 inhibitor) and voriconazole (CYP2B6 and CYP2C19 inhibitor). Model performance quantification showed 20/20 DGI ratios of hydroxybupropion to bupropion AUC ratios (DGI AUCHBup/Bup ratios), 12/13 DDI AUCHBup/Bup ratios, and 7/7 DDGI AUCHBup/Bup ratios within 2-fold of observed values. The developed model is freely available in the Open Systems Pharmacology model repository.

Allelic and genotype frequencies of major CYP2B6 polymorphisms in the Pakistani population.

BackgroundCytochrome P450 (CYP2B6) is an important enzyme that metabolizes about 3.0% of therapeutic drugs. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. The genetic polymorphisms in the CYP2B6 gene have earlier been studied in many populations, but the data are lacking for the Pakistani population. This research study aimed to determine the frequencies of the three of the most important variant alleles and genotypes of the CYP2B6 gene in the Pakistani population.MethodsBlood was withdrawn from healthy volunteers after taking informed consent. DNA was extracted using commercial kits, and allelic and genotype frequencies were determined after PCR amplification followed by restriction fragment length polymorphism (RFLP) and gel electrophoresis.ResultsOur results show a minor allele frequency of 33.8% for CYP2B6*6, 25.8% for CYP2B6*4, 6.5% for CYP2B6*3, whereas wild‐type genotype frequency was 48.57% for CYP2B6*6, 59.79% for CYP2B6*4, and 90.20% for CYP2B6*3. A significant interethnic variation was also observed.ConclusionsOur results suggest that the frequency of poor metabolizers of CYP2B6, especially *6 variant, is significant enough in the Pakistani population to be given an important consideration when drugs metabolized by this enzyme are prescribed.

ABCB1, CYP2B6, and CYP3A4 genetic polymorphisms do not affect methadone maintenance treatment in HCV-positive patients.

The aim of this study was to determine the influence of ABCB1, CYP2B6, and CYP3A4 genetic polymorphisms on methadone metabolism in patients with hepatitis C virus (HCV) undergoing methadone maintenance treatment (MMT). The study included 35 participants undergoing MMT, who were divided in three groups: HCV-positive (N=12), HCV-negative (N=16), and HCV clinical remission (CR) (N=7). The concentrations of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were determined with gas chromatography-mass spectrometry. The patients were genotyped for ABCB1 rs1045642, CYP2B6 rs3745274, CYP3A4 rs2242480, and CYP3A4 rs2740574 polymorphisms. Differences between single nucleotide polymorphism (SNP) genotypes and methadone-to-EDDP ratio were analysed with one-way ANOVA, which showed no significant difference between the genes (p=0.3772 for ABCB1 rs1045642, p=0.6909 for CYP2B6 rs3745274, and p=0.6533 for CYP3A4 rs2242480). None of the four analysed SNP genotypes correlated with methadone-to-EDDP concentration ratio. A major influence on it in hepatitis C-positive patients turned out to be the stage of liver damage.

Association of cytochrome P450 1B1 gene polymorphisms and environmental biomarkers with hypertension in Slovak midlife women.

This study investigated the association of the Leu432Val and Asn453Ser CYP1B1 polymorphisms and selected environmental biomarkers with hypertension (HT) in Slovak midlife women. We studied 575 women. Divided according to their blood pressure status: 255 with HT and 320 without HT. All data was obtained by using standard anthropometric, genetic methods and analyzed by regression models to adjust for HT risk factors such as age, obesity, smoking, and level of education. Our findings revealed that CYP1B1 Leu432Val polymorphism was associated with HT, whereas no association was found between Asn453Ser polymorphism and HT. Women with at least one Val allele had significantly higher odds of HT compared to women with the Leu/Leu genotype in the total sample (Exp(B) = 1.82, CI 1.16-2.84, P = 0.009). After dividing women by menopausal status and the presence of HT environmental risk factor, the association between CYP1B1 polymorphism and HT was observed in pre/perimenopausal women (Exp(B), 2.36; 95% CI 1.13-4.92; P = 0.02), smokers (Exp(B), 3.40; 95% CI 1.48-7.82; P = 0.004), abdominal obesity (Exp(B), 2.41; 95% CI 1.23-4.75; P = 0.01) and in women with only basic education (Exp(B), 4.20, 95% CI 1.12-15.71; P = 0.03). However, general linear models did not reveal a statistically significant interactions between CYP1B1, menopausal status, and HT risk factors and their common association with HT (P > 0.05). In this pilot study, we have provided novel data that supports the significant association of CYP1B1 Leu432Val gene polymorphism with HT in Slovak midlife women.

Effects of CYP2B6 polymorphisms on plasma nevirapine concentrations: a systematic review and meta-analysis

Cytochrome P450 (CYP) is involved in the metabolism of nevirapine (NVP); especially, CYP2B6 has been known to be one of the main enzymes involved in NVP metabolism. The objective of this study was to investigate the effects of CYP2B6 variants on plasma concentrations of NVP by a systematic review and meta-analysis. A search for qualifying studies published until April 2020 was conducted using the EMBASE, PubMed, and Web of Science databases. The mean difference (MD) and 95% confidence intervals (CIs) were calculated. Data analysis was performed using R Studio (version 3.6) and Review Manager (version 5.3). In total, data from six studies involving 634 patients were analyzed in the systematic review and five studies in the meta-analysis. We found that carriers of the CYP2B6 516TT genotype had a 2.18 µg/mL higher NVP concentration than did the GG or GT (95% CI 1.28–3.08). In the respective comparisons of the three genotypes, it was found that the MD was 1.87 µg/mL between the TT and GT groups, 2.53 µg/mL between TT and GG, and 0.60 µg/mL between GT and GG. This meta-analysis confirmed that CYP2B6 polymorphisms was associated with plasma NVP concentrations. Therefore, CYP2B6 genotyping may be useful to predict the responses to NVP.

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz.

BackgroundDolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART).MethodsWe studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm.ResultsThere were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype.Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

Association of Vitamin D Pathway Gene CYP27B1 and CYP2R1 Polymorphisms with Autoimmune Endocrine Disorders: A Meta-Analysis.

Studies on organ-specific autoimmune endocrine disorders showed correlations between disease risks and vitamin D pathways gene variants, such as CYP27B1 rs10877012 and rs4646536, or CYP2R1 rs10741657 single nucleotide polymorphisms. However, previous works presented inconsistent conclusions. Our study aimed at assessing the association of CYP27B1 and CYP2R1 polymorphisms with autoimmune endocrine disorder susceptibility using the meta-analysis method. Case-control studies of the subject of interest were identified from the databases Pubmed, Embase, Cochrane Library, and China National Knowledge Infrastructure. Studies that met inclusion and quality criteria were pooled. Observational outcomes were diagnosis of autoimmune Addison's disease, Graves disease, Hashimoto thyroiditis, or type 1 diabetes mellitus. Statistical analysis was performed using software STATA 16.0. A total of 14 studies involving 12 929 patients (2243 autoimmune Addison disease, 1253 Graves disease, 612 Hashimoto thyroiditis, 8821 type 1 diabetes), and 12 907 healthy control subjects were pooled for meta-analysis. The rs10877012 minor allele A and its homozygote and heterozygote conferred low overall disease risk (OR [odds ratio] = 0.748, 95% CI [confidence interval] 0.620-0.902 in dominant model; OR = 0.709, 95% CI 0.571-0.879 in recessive model; OR = 0.777, 95% CI 0.674-0.895 in the allele model). The population carrying rs4646536 minor allele C and its homozygote and heterozygote showed decreased overall autoimmune endocrine disorders risk (OR = 0.849, 95% CI 0.748-0.963; OR = 0.868, 95% CI 0.790-0.955; OR = 0.915, 95% CI 0.875-0.957 in the dominant, recessive, and allele model, respectively). No significant genetic association was found for rs10741657. Our study suggested CYP27B1 polymorphisms rs10877012 minor allele A and rs4646536 minor allele C were negatively related to susceptibilities of organ-specific autoimmune endocrine diseases.