Polymorphic Cytochrome P450 Research Articles

Generation of cytochrome P450 polymorphic human induced pluripotent stem cell lines with defective CYP activities

Single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP) isoenzymes alter drug metabolism and pharmacodynamics. In particular, several SNPs within CYPs decrease CYP activities, resulting in a high plasma concentration of drugs and increasing adverse effect of commonly used drugs. Here, we generated two different human induced pluripotent stem cell (hiPSC) lines, which retain defective CYP2C19 or CYP3A5 activities individually. These two hiPSC lines could be valuable sources for understading the interindividual variability in drug responses caused by SNP-induced alteration in CYP activites.

Association study between a genetic polymorphism in cytochrome P450 19 gene rs10046 and colon and rectal cancer

Objective To investigate the relationship between the polymorphism of cytochrome P450 19 (CYP19) gene rs10046 and the risk of colon and rectal cancer. Methods Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)to analyze gene polymorphism in CYP 19 gene rs10046 in 198 cases of colon and rectal cancer patients (case group)and 309 cases of healthy controls (control group). The genotype frequency and relative risk of CYP19 gene rs10046 between the two groups were compared and the relationship with the clinicopathological features of colorectal cancer was analyzed. Results In case group, the prevalence rates of CYP19 rs10046 genotypes C/C, C/T and T/T were 28.3%, 44.4% and 27.3%, respectively, and 17.2%, 51.8% and 31.1% in the control group, respectively, with statistical significant difference (P<0.05). Compared with wild-type C/C, the susceptibility of colorectal cancer with the genotypes of C/T and T/T was decreased by 0.521 (95% CI: 0.330-0.822) and 0.532 (95% CI: 0.322-0.880) respectively. Moveover, in the non-smoking group, the risk of colorectal cancer with genotype T/T or C/T was decreased by 0.409 (95% CI: 0.210-0.798) compared with genotype C/C. The interaction was not exist in smoking group. Conclusions The polymorphism of CYP19 gene rs10046 is related to the susceptibility of colon and rectal cancer. The T/T, C/T genotype of CYP19 rs10046 decrease the risk of colon and rectal cancer, and which might be the protective factor of colon and rectal cancer. Key words: Polymorphism, genetic; Cytochrome P-450 enzyme system/GE; Colorectal neoplasms/GE

Chemical Induced Liver Injury: Types, Mechanisms and Biomarkers

Liver is a primary organ involved in biotransformation of foods and drugs. Liver diseases are a major worldwide problem; Hepatic disorders are mainly caused by toxic chemicals, e.g. - alcohol, carbon tetra chloride, anticancer agent, analgesic, anti-inflammatory drugs, anti-tuberculosis agent and heavy metals. Various risk factors for liver damage include age, gender, alcoholism, nutrition and genetic polymorphisms of cytochrome P450 have also been considered. The present review enumerate various hepatic diseases, risk factors and chemicals induced hepatic injury via different mechanical pathway as well as numerous biochemical changes viz. serum biomarkers, proteomics biomarkers, genomic biomarkers, metabolic biomarkers and micro RNA. This review could be immensely useful for researchers especially for pharmacologists, toxicologist working on hepatotoxicity and drug research organization.

Cytochrome P450 genotype-guided drug therapies: An update on current states.

Over the past 2 decades, knowledge of the role and clinical value of pharmacogenetic markers has expanded so that individualized pre-emptive therapy based on genetic background of patients could be within reach for clinical implementation. This is evidenced from the frequent updating of drug labels that incorporates pharmacogenetic information (where compelling data become available) by the regulatory agencies (such as the US FDA), and the periodical publication of guidelines of specific therapeutic recommendations based on the results of pharmacogenetic tests by the pharmacogenetics working groups or consortiums of professional bodies. Clinical relevance of the cytochrome P450 (CYP) polymorphism related to dose, effectiveness and/or toxicity of key drugs are presented in this review, including that of warfarin, clopidogrel, tricyclic antidepressants, and proton pump inhibitors. Prospect for routine clinical application of CYP genotyping before prescribing drugs is still currently unclear due to challenges and barriers associated with availability of well-defined and validated pharmacogenetic studies, the interpretation, result reporting and potential error of genotype testing, involvement of non-genetic factors, and other patient's demographic and disease conditions. Further studies to provide additional supporting clinical data and acceleration of pharmacogenetic testing standards and techniques should help improve the evidence base needed for clinical utility and hence move the implementation of genotype-guided therapy in clinical practice a step closer to reality.

The association between CYP2C9/2C19 polymorphisms and phenytoin maintenance doses in Asian epileptic patients: A systematic review and meta-analysis .

Therapeutic response to phenytoin (PHT), a first-line antiepileptic drug (AED), is highly variable, in part likely due to genetic factors. Genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C19 are expected to affect the metabolism of PHT and consequently affect its maintenance doses. We aimed to clarify the effects of genetic polymorphisms in both enzymes on daily PHT maintenance dosage in Asian epileptic patients by meta-analysis. A systematic literature search was conducted in PubMed and EMBASE for relevant studies published prior to April 14, 2017. RevMan 5.2.3 software was used to analyze the relationship between CYP2C9/2C19 polymorphisms and PHT maintenance doses. A total of 6 studies with 993 patients fulfilling the inclusion criteria were included in our meta-analysis. The homozygous and heterozygous CYP2C19 mutation group (i.e., CYP2C19*2/*2, CYP2C19*3/*3, or CYP2C19*2/*3 group) required significant decrease of PHT maintenance dose. The starting maintenance dose suggested in this group is 4.38mg/kg/day. Patients with heterozygous CYP2C9 or both heterozygous CYP2C9 and CYP2C19 showed a trend but not a statistically-significant decrease of PHT dose, but dosage adjustment was recommended. The meta-analysis indicates that CYP2C9 and CYP2C19 polymorphisms are associated with lower PHT maintenance dosage in Asian epileptic patients. Ethnic differences can influence PHT maintenance dose. .

Potent Potassium-competitive Acid Blockers: A New Era for the Treatment of Acid-related Diseases.

Conventional proton pump inhibitors (PPIs) are used as a first-line therapy to treat acid-related diseases worldwide. However, they have a number of limitations including slow onset of action, influence by cytochrome P450 polymorphisms, unsatisfactory effects at night, and instability in acidic conditions. Alternative formulations of conventional PPIs have been developed to overcome these problems; however, these drugs have only introduced small advantages for controlling acid secretion compared to conventional PPIs. Potassium-competitive acid blockers (P-CABs) were developed and have beneficial effects including rapid, long-lasting, and reversible inhibition of the gastric hydrogen potassium ATPase, the proton pump of the stomach. Vonoprazan was recently innovated as a novel, orally active P-CAB. It is currently indicated for the treatment of gastric and duodenal ulcers, reflux esophagitis, and prevention of low-dose aspirin- or nonsteroidal anti-inflammatory drug-related gastric and duodenal ulcer recurrence in Japan. Vonoprazan does not require enteric coating as it is acid-stable, and it can be taken without food because it is quickly absorbed. Vonoprazan accumulates in parietal cells under both acidic and neutral conditions. It does not require an acidic environment for activation, has long-term stability at the site of action, and has satisfactory safety and tolerability. Thus, vonoprazan may address the unmet medical need for the treatment of acid-related diseases.

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics are dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p=0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after one month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

Associations of polymorphisms of CYP2D6 and CYP2C9 with early onset severe pre-eclampsia and response to labetalol therapy.

Early onset preeclampsia (PPE) contributes to life-threatening maternal complications and fetal demise. Pharmacogenomics is a precision medicine, and metabolizing enzymes responsive to antihypertensive remains understudied. The aim of this study was to evaluate the associations of polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with PPE and the relationship among CYP2D6, CYP2C9 polymorphisms and response to labetalol therapy. Totally 105 gravidas diagnosed with PPE (case) and 103 healthy gravidas (control) were recruited between August 2013 and July 2016. Labetalol was given to control blood pressures (BP) with PPE. If labetalol administration alone did not exceed the mean dose and effectively controlled the BP, it would be considered to be valid (n = 75). Genotype and allele frequencies of CYP2C9 gene (rs1057910 and rs4918758) and CYP2D6 gene (rs1065852, rs28371725, rs35742686, and rs3892097) were analyzed by TaqMan PCR. Differences in the genotype and allele frequencies were compared between case-control groups, and the responsive and nonresponsive to labetalol in PPE. Out of six variants, only CC and CT genotypes of the CYP2D6 variants (rs28371725) in PPE were significantly higher than those in the control group [18.1% (19/105) vs 14.6% (15/103); 56.2% (59/105) vs 42.7% (44/103); χ2 = 6.707]. However, there were no differences in maternal age, diastolic pressure, BMI, BW, serum triglyceride, and creatinine were observed among women with CC, CT, or TT genotype of CYP2D6 gene rs28371725 in the experimental group (all P > 0.05). Compared with the gravidas with CT or TT genotype of CYP2D6 gene rs28371725, those with CC genotype had longer gestational age [(32.5 ± 2.1) vs (29.5 ± 1.8) and (29.8 ± 2.2)weeks] and higher plasma albumin [(27.2 ± 9.3) vs (20.3 ± 10.4) and (22.5 ± 7.4)g/L], but lower systolic pressure and 24h urine protein (LSD test, all P < 0.05). The G allele frequency in CYP2D6 gene rs1065852 nonresponsive to labetalol group was higher than that in responsive labetalol group [93.3% (56/60) vs 76.0% (114/150), χ2 = 8.351, P = 0.004]. The polymorphism of CYP2D6 gene rs28371725 may be associated with PPE, and the allele of G in CYP2D6 gene rs1065852 may be associated with the efficacy of labetalol in treatment of PPE.

Fast Screening Technology for Drug Emergency Management: Predicting Suspicious SNPs for ADR with Information Theory-based Models.

The genetic polymorphism of Cytochrome P450 (CYP 450) is considered as one of the main causes for adverse drug reactions (ADRs). In order to explore the latent correlations between ADRs and potentially corresponding single-nucleotide polymorphism (SNPs) in CYP450, three algorithms based on information theory are used as the main method to predict the possible relation. The study uses a retrospective case-control study to explore the potential relation of ADRs to specific genomic locations and single-nucleotide polymorphism (SNP). The genomic data collected from 53 healthy volunteers are applied for the analysis, another group of genomic data collected from 30 healthy volunteers excluded from the study are used as the control group. The SNPs respective on five loci of CYP2D6*2,*10,*14 and CYP1A2*1C, *1F are detected by the Applied Biosystem 3130xl. The raw data is processed by ChromasPro to detect the specific alleles on the above loci from each sample. The secondary data are reorganized and processed by R combined with the reports of ADRs from clinical reports. Three information theory based algorithms are implemented for the screening task: JMI, CMIM, and mRMR. If a SNP is selected by more than two algorithms, we are confident to conclude that it is related to the corresponding ADR. The selection results are compared with the control decision tree + LASSO regression model. In the study group where ADRs occur, 10 SNPs are considered relevant to the occurrence of a specific ADR by the combined information theory model. In comparison, only 5 SNPs are considered relevant to a specific ADR by the decision tree + LASSO regression model. In addition, the new method detects more relevant pairs of SNP and ADR which are affected by both SNP and dosage. This implies that the new information theory based model is effective to discover correlations of ADRs and CYP 450 SNPs and is helpful in predicting the potential vulnerable genotype for some ADRs. The newly proposed information theory based model has superiority performance in detecting the relation between SNP and ADR compared to the decision tree + LASSO regression model. The new model is more sensitive to detect ADRs compared to the old method, while the old method is more reliable. Therefore, the selection criteria for selecting algorithms should depend on the pragmatic needs.

59 Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics

59 Identification of Cytochrome P450 Polymorphisms in Burn Patients and Impact on Fentanyl Pharmacokinetics

Manipulating Cytochrome P450 Enzymes: New Perspectives for Cancer Treatment

Increasing drug efficiency and reducing drug overall toxicity are two of the main goals of today`s drug chemotherapy of cancer. In general this could be achieved by searching new ways for selective active drug accumulation in cancer cells by manipulating local drug metabolism or delivery. In this short review, on the basis of the main directions described by McFadyen et al. (Mol Cancer Ther 2004; 3(3): 363-371), new data is reported for localization and expression of cytochrome P450 enzymes in human tumors, development of cytochrome P450-based and gene-directed enzyme activated prodrugs, antisense-based P450 and immune-based therapy, cytochrome P450 polymorphism in development of anticancer drugs. New discoveries of molecular biology of cancer give us hope for more successful development of modern cancer chemotherapy. Biomed Rev 2017; 28: 120-124. Keywords: cytochrome P450 isoforms, cancer cells, drug metabolism, drug delivery

Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers.

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC0-t , Cmax and t1/2 of aripiprazole were higher and clearance of aripiprazole, AUC0-t of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC0-t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC0-t of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p=0.023) and AUC0-t (p=0.039) and Cmax of dehydro-aripiprazole (p=0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p=0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC0-t of aripiprazole (p=0.001), especially nausea/vomiting, which were more common in women (p=0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p=0.034; p=0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.

Genetic and Demographic Outcomes in a Population of Patients with Headache and Facial Pain

Background: Pharmacogenetics information about cytochrome p450 (CYP450) polymorphism in patients with headaches is limitedly reported. Similarly, the genetic factors linking various headache types and vascular disorders are poorly described. We aimed to characterize the genetic profile of a cohort of headache and facial pain subjects. Methods: Medical records of consecutive headache subjects that underwent PersonaGeneTM testing were reviewed. PersonaGeneTM panel assessed CYP450, apolipoprotein E (ApoE), methylene tetrahydrofolate reductase (MTHFR), Factor II, Factor V Leiden and Vitamin K epoxide reductase complex subunit 1 (VKORC1). Demographic information, headache diagnosis and genetic profiling were analyzed and compared with data obtained from the general population. Results: Out of 130 headache patients, 91.3% were Caucasian and 70.8% had migraine. Compared to the general Caucasian population, our Caucasian headache patients were significantly different for CYP3A4/A5 and CYP2D6 (p Conclusion: Distinctive profiles for CYP450, ApoE, Factor V Leiden and VQORC1 were observed in our Caucasian headache cohort. These results may impact headache subjects’ pharmacological treatment options and vascular risk ascertainment.

Polymorphisms of CYP3A5 Affect Serum Levels and Maintenance Doses of Tacrolimus in Myasthenia Gravis Patients

Objectives: To evaluate the influences of polymorphisms of cytochrome P450 (CYP) 3A5 (A6986G, CYP3A5*3) on serum levels of tacrolimus and cyclosporine (CyA) in patients with myasthenia gravis (MG). Methods: This study included 74 MG patients treated with tacrolimus (n=65) or CyA (n=22). Genomic DNA was extracted and amplified with specific primers, and CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 DNA sequencer. We measured blood trough level (C0) of tacrolimus and CyA. Clinical disabilities were evaluated with the MG-ADL scale. Results: For tacrolimus C0, the CYP3A5*3/*3 genotype was associated with higher levels than the CYP3A5*1/*3 genotypes (7.1 ng/ml versus 2.9 ng/ml; P<0.0001) and CYP3A*1/*1 (7.1 ng/ml versus 1.3 ng/ml; P<0.0004). The improvement in the mean MG-ADL scores tended to be better in MG patients with the CYP3A5*3/*3 or CYP3A5*1/*3 than those with CYP3A5*1/*1. For the CyA concentrations, CYP3A5 genotypes did not have significant effects. Conclusion: In MG patients, CYP3A5 polymorphism significantly affects serum levels of tacrolimus and thereby treatment effects, but not those of CyA. The maintenance dose of tacrolimus should be determined considering CYP3A5 polymorphism.

Detection of Cytochrome P450 Polymorphisms in Breast Cancer Patients May Impact on Tamoxifen Therapy

Background:Breast cancer is the most common cancer among women worldwide. Tamoxifen (TAM), a selective estrogen receptor modulator, is widely used in its treatment. TAM is metabolized by cytochrome P450 (CYP450) enzymes, including CYP2D6, CYP3A5 and CYP2C19, whose genetic variations may have clinicopathological importance. However, reports on the association of various P450 polymorphisms with certain cancers are contradictory.Methods:We here investigated whether the prevalence of the four most common polymorphism in the CYP2D6*4 (G1934A), CYP2D6*10 (C188T), CYP3A5*3 and CYP2C19*2 alleles has any link with breast cancer using genomic DNA and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis.Results:Prevalences of CYP2D6*4, CYP2D6*10 and CYP2C19*2 genotypes were differed significantly (P = 0.01 and P = 0.004) between breast cancer patients and controls. The CYP3A5*3 genotype did not demonstrate statistically significant variation.Conclusion:Polymorphisms in CYP2 appear to be associated with breast cancer risk. Our data taken together with other reports indicates that drug resistance gene polymorphisms might be indicators of response to tamoxifen therapy in breast cancer cases.

Cytochrome P-450 Polymorphisms and Clinical Outcome in Patients with Non-Small Cell Lung Cancer

Lung cancer is an increasing worldwide public health problem. Most patients with lung cancer have non-small cell lung cancer (NSCLC). These patients are mainly treated with standard platinum-based chemotherapy. Poor response and great inter-individual variety in treatment response occurs among these patients. There is accumulating evidence to support the hypothesis that genetic polymorphisms alter the drug response and survival. Cytochrome P450 (CYP) enzymes metabolize antineoplastic drugs and are involved in drug resistance. Polymorphic CYPs have altered enzyme activities and thus they may influence the response to chemotherapy and survival in patients with lung cancer. In the current review, recent findings with respect to the role of mainly CYP1A1, CYP1B1, CYP2D6, CYP2E1 and CYP3A4 gene polymorphisms in response to chemotherapy and survival in patients with NSCLC have been provided, which could be useful for clinicians in the prognosis of these patients who are mainly treated with platinum-based chemotherapy.

CYP2E1 Gene Polymorphisms Related to the Formation of Coronary Artery Lesions in Kawasaki Disease.

Kawasaki disease (KD) is an acute febrile systemic vasculitis that disturbs coronary arteries. Patients' risks of adverse cardiovascular events and subclinical atherosclerosis have been found to significantly increase with polymorphisms of the human cytochrome P450. This current study aims to research the possible relationship between cytochrome P450, family 2, subfamily E and polypeptide 1 (CYP2E1) polymorphisms with KD. We selected 6 tag single-nucleotide polymorphisms (SNPs) of the CYP2E1 gene for TaqMan allelic discrimination assay in 340 KD patients and performed analysis on the clinical phenotypes and coronary artery lesions (CALs). CAL associations of tag SNPs were adjusted for age and gender in the logistic regression. The KD patients with a CC genotype of rs915906 demonstrated a greater proportion of CAL formation (P = 0.009). Furthermore, the GG genotype frequencies of rs2070676 showed a significantly greater risk for CAL formation in KD patients (P = 0.007). However, the SNPs of the CYP2E1 gene did not influence CAL formation in the participating KD patients either with or without high-dose acetylsalicylic acid. Using the expression quantitative trait locus analyses, we found that the SNPs associated with CAL formation in KD also affected CYP2E1 expression in certain cell types. This study is the first to find that the risk of CAL formation is related to CYP2E1 gene polymorphisms in KD patients.

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OBJECTIVES/SPECIFIC AIMS: Patients with epilepsy often combine their antiepileptic drugs (AEDs) with complementary medicine (CM). They use CM to treat their symptoms of comorbidities disorder, to reduce the side effect of the AEDs or trying to achieve better control of their seizures. However, the inconsistent patters of the use of CM among countries have been attributed to cultural and socio-economic factors and limited studies have explored biological factors. The aim of this study is to determinate whether or not there is an association between having genetic polymorphisms on candidate pharmacogenes for drug-metabolizing enzymes cytochrome P450 (CYP) and the use CM among patients with drug-resistant epilepsy (DRE). METHODS/STUDY POPULATION: In this cross-sectional study, patients will be recruited in the Epilepsy Clinic in the Medical Science Campus of University of Puerto Rico and in private Neurology clinics. To participate in this study, patients need to have both parents of Puerto Rican origin to be defined as Puerto Rican and have a diagnosis of DRE, defined as persistent seizures after at least 2 good trials of the proper drugs at the right dose. After the patient sign, the inform consent, a buccal swap will be collected, and the patient will complete a questionnaire. In the questionnaire, the patient will do a self-report about the use of CM (including natural products, meditation, yoga, and others), frequency of use and socio-economic information. Polymorphisms for CYP 2D6, 2C9, 2C19, or 1A2 will be determined using TaqMan® SNP Genotyping Assays. Data analysis will include descriptive statistical, χ2 and ANOVA test. RESULTS/ANTICIPATED RESULTS: We expected to determine the frequency distribution of functional polymorphisms on CYPs among patients with DRE who are either using CM and AEDs or standard care (AEDs). Quantified the use of CM and ascertain if there is an association with the CYPs polymorphisms. DISCUSSION/SIGNIFICANCE OF IMPACT: This study is novel, because we will use an objective test, pharmacogenetics approach to rule out biological factors associated with the use of Complementary Medicine by patients’ DRE. The study will provide evidence for prospective study using specifics Complementary Medicine guiding by genotyping.

Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen.

Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual’s capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings.Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin. Robust coefficients of determination (R2) were estimated for endoxifen (E) or metabolic ratio endoxifen/desmethyl-TAM (E/DMT) as dependent and different CYP2D6 phenotype assignments as independent variables. Allele activity scores (ASs) were modified with respect to a reduced ∗10 allele activity. Predictability of endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL was investigated by receiver operating characteristic (ROC) analysis.Results: CYP2D6 diplotypes (N = 898) were strongly associated with E and E/DMT independent of age (P < 10-15). Across all ethnicities, 68–82% inter-patient variability of E/DMT was explained by CYP2D6 diplotype, while plasma endoxifen was predictable by 39–58%. The previously used codeine specific phenotype classification showed worse prediction for both endpoints particularly in Asians (median R2< 20%; P < 10-9). Downgrading of ∗10 activity slightly improved the explanatory value of metabolizer phenotype (P < 0.002). Endoxifen plasma concentrations above the clinical threshold of 5.9 ng/mL were achieved in 82.3% of patients and were predictable (96% sensitivity, 57% specificity) by CYP2D6 diplotypes with AS > 0.5, i.e., omitting PM/PM and PM/IM patients.Conclusion: The CYP2D6 explanatory power for active drug level assessment is maximized by TAM-specific phenotype assignments while a genotype cutoff that separates PM/PM and PM/IM from the remaining patients may improve clinical benefit via increased endoxifen concentrations.

ビタミンDとシトクロムP450の遺伝子多型( 「ビタミンと遺伝子多型」-ビタミンD-)

ビタミンDとシトクロムP450の遺伝子多型( 「ビタミンと遺伝子多型」-ビタミンD-)