Thalidomide metabolism by the CYP2C subfamily.

PURPOSE: This research investigated the biotransformation of thalidomide by cytochrome P-450 (CYP). EXPERIMENTAL DESIGN: We used liver microsomes from humans and/or animals and the recombinant specific CYP isozymes to investigate CYP-mediated metabolism of thalidomide. RESULTS: Thalidomide was biotransformed into 5-hydroxythalidomide (5-OH) and diastereomeric 5'-hydroxythalidomide (5'-OH) by liver microsomes. The human liver microsomes with higher CYP2C19 activity formed more metabolites than those with lower CYP2C19 activity and had less activity in metabolite formations than those from rats. Recombinant human CYP2C19 and rat CYP2C6 isozymes were primarily responsible for forming these metabolites, and the male rat-specific CYP2C11 formed only 5'-OH. 5-OH was subsequently hydroxylated to 5,6-dihydroxythalidomide by CYP2C19, CYP2C9, and CYP1A1 in humans and by CYP2C11, CYP1A1, CYP2C6, and CYP2C12 in rats. Incubations with S-mephenytoin and omeprazole, substrates of CYP2C19, inhibited metabolism by human liver microsomes, supporting the involvement of CYP2C19. alpha-Naphthoflavone, an inhibitor of CYP1A, simultaneously stimulated the 5-OH formation and inhibited cis-5'-OH formation catalyzed by human liver microsomes. The contribution of the CYP2C subfamily was supported by the immunoinhibition study using human liver microsomes. When we used the microsomes from treated rats, the metabolite formations did not increase by inducers for CYP1A, CYP2B, CYP2E, CYP3A, or CYP4A, suggesting that these could not be involved in the main metabolic pathway in rats. CONCLUSIONS: We discovered that the polymorphic enzyme CYP2C19 is responsible for 5- and 5'-hydroxylation of thalidomide in humans. In rats, thalidomide was hydroxylated extensively by CYP2C6 as well as the sex-specific enzyme CYP2C11.     

CYP2C19 pharmacogenetics in advanced cancer: compromised function independent of genotype

CYP2C19 is a drug-metabolising enzyme involved in the metabolism of a number of chemotherapeutic agents including cyclophosphamide. Variants of the CYP2C19 gene result in a loss of function polymorphism, which affects approximately 3% of the Caucasian population. These individuals are poor metabolisers (PM) of a wide range of medications including omeprazole (OMP). In healthy subjects PM can be identified through homozygous variant genotype. However, a discordance between CYP2C19 genotype and phenotype has been reported previously in a small study of cancer patients. To investigate whether CYP2C19 activity was decreased in patients with advanced cancer, CYP2C19 genotype was determined in 33 advanced cancer patients using PCR-RFLP analysis for the two important allelic variants (*2,681G>A and *3,636G>A) and the activity of the enzyme was evaluated using the CYP2C19 probe drug OMP. The activity of the drug-metabolising enzyme CYP2C19 was severely compromised in advanced cancer patients, resulting in a PM status in 37% of the patients who had normal genotype. This is significantly (P<0.0005) higher than that would be predicted from the genotypic status of these patients. There was no evidence of a correlation between compromised CYP2C19 activity and any of the proinflammatory cytokines or acute phase response proteins studied. However, there was preliminary evidence of an association between PM status and low body mass (P=0.03). There is increasing interest in using pharmacogenetics to 'individualise medicine', however, the results of this study indicate that in a cancer population genotyping for CYP2C19 would significantly underestimate the number of phenotypic PM of drugs, such as cyclophosphamide, which may be metabolised by this enzyme.     

致癌物代谢酶基因（CYP2C19、GSTT_1）多态性与哈萨克族人群食管癌发病风险关系的研究

目的探讨、相代谢酶基因多态性与新疆哈萨克族人群食管癌发病风险的关系。方法收集经组织病理学确诊的哈萨克族食管鳞癌新发病例88例外周血液标本,提取DNA后用PCR-RFLP技术检测CYP2C19、GSTT1基因多态性。结果食管癌组和对照组中CYP2C19m1、CYP2C19m2基因各型之间差异无统计学意义（P〉0.05）,但食管癌组S-美芬妥英慢代谢者（PM）的患病率为26.1%,为正常对照组11.1%约2倍多,两者差异有统计学意义（χ2=5.72,P〈0.05,相对危险度OR=2.831,95%可信度CI：1.180～6.793）。GSTT1基因缺失型（-）和正常型（＋）频率在对照组中分别为45.4%和54.2%,在哈萨克族食管癌组中分别为64.8%和35.2%,两组间的频率分布差异有统计学意义（P〈0.05,OR=2.173,95%CI：1.149～4.110）。结论相代谢酶基因CYP2C19在哈萨克族人群中具有遗传多态性,CYP2C19m1和CYP2C19m2是两个相互独立的突变型等位基因,CYP2C19慢代谢者参与了食管癌致癌物的灭活,其活性降低时可增加患食管癌的易感性。相代谢酶基因GSTT1基因缺失型（-）可能是哈萨克族人群患食管癌重要的生物标志。对哈萨克族人群进行、相代谢酶基因分型,有助于筛选食管癌发生的高危人群,可为食管癌的预防和早期诊断提供科学依据。     

CYP2C19 Genotype Could be a Predictive Factor for Aggressive Manifestations of Hepatocellular Carcinoma Related with Chronic Hepatitis B Infection in Thailand

Background: Chronic hepatitis B virus (HBV) infection related hepatocellular carcinoma (HCC) is a majorhealth problem in the Asia-Pacific region including Thailand. Several factors have been proposed as contributingto hepatocarcinogenesis. This study was aimed to investigate the impact of CYP2C19 genotypic polymorphismin HCC related to chronic HBV infection in Thailand. Materials and Methods: A cross-sectional study wasperformed between April 2014 and January 2015. Chronic HBV patients with HCC (n=50) and without HCC(n=50) were included. Clinical information and blood samples of all patients were collected. The CYP2C19genotype was determined by polymerase chain reaction-restriction fragment length polymorphism method, andwas classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). Results:The CYP2C19 genotype frequencies of RM, IM and PM in HBV patients were found to be 19/50 (38%), 25/50(50%) and 6/50 (12%), respectively. The CYP2C19 genotype frequencies of RM, IM and PM in HBV with HCCpatients were 21/50 (42%), 25/50 (50%) and 4/50 (8%), respectively. The distribution of CYP2C19 genotype wasnot different between patients with and without HCC. Interestingly, among HBV with HCC patients, the RMgenotype of CYP2C19 tended to increase risk of aggressive manifestation (OR=2.89, 95%CI=0.76-11.25, P-value= 0.07), compared with non RM genotype carriers. Conclusions: CYP2C19 genotype IM was the most commongenotype in Thai patients with chronic HBV infection. In addition, genotype RM could be an associated factorfor aggressive presentation in HCC related to chronic HBV infection.     

CYP2D6 gene polymorphism in caucasian smokers: lung cancer susceptibility and phenotype-genotype relationships

Individual susceptibility to smoking-related cancers is proposed to partly depend on a genetically determined ability to metabolise tobacco carcinogens. We previously reported on the association between the activity of the xenobiotic-metabolising enzyme CYP2D6 and lung cancer risk in a hospital-based case-control study among French Caucasian smokers. Here we extended the study to address the effect of four gene-inactivating mutations (CYP2D6(*)3, (*)4, (*)5 and (*)16) and the gene duplication of the CYP2D6 gene (CYP2D6(*)2x2 or CYP2D6(*)1x2) on lung cancer risk in the same population (150 patients with primary lung carcinoma of squamous cell or small cell histology and 172 controls). The risk of lung cancer associated with the CYP2D6 poor metaboliser genotype (odds ratio 1.5, 95% confidence interval 0.5-4.3) did not differ from that in the reference category of extensive metaboliser and ultra-rapid metaboliser genotypes combined. Lung cancer risks for the CYP2D6 PM genotype amongst light smokers (tobacco consumption 20 g/day) were not significantly different. The present findings agree with the discrepancy between the phenotype-based and genotype-based studies indicated by the recent meta-analyses.     

CYP450 polymorphisms predict clinic outcomes to vinorelbine-based chemotherapy in patients with non-small-cell lung cancer

CYP2C19*2(G681A), CYP2C19*3(G636A), CYP2D6*4(C188T), CYP2D6*2(C2938T, G4268C), CYP3AP1*3- G44A and CYP3A5*3(A22893G) are the most common polymorphisms detected among Chinese that may influence the efficacy of vinorelbine-based therapies to treat non-small-cell lung cancer (NSCLC). We detected the genotypes of these polymorphisms by PCR-RFLP in 59 patients with NSCLC and assessed their responses to vinorelbine. CYP2D6*4(C188T), CYP3AP1*3 (G -44 A) and CYP3A5*3 were found to be associated with response to vinorelbine. For the 2D6*4 polymorphism, the 18 of 32 (56.25%) patients with homozygous (C/C) responded to this therapy, while 6 of 27 (22.22%) of those heterozygous (C/T) at this site responded. (chi2=5.68, p < 0.05) For the 3AP1*1/*3 polymorphism, 12 of 42 (28.57%) patients with homozygous (A/A) responded, while 12 of 17 (70.59%) with heterozygous (A/G) and homozygous (G/G) responded (chi2=7.19, p < 0.01). CYP3A5*3 polymorphism has a result corresponding to 3AP1*3 polymorphism. Other polymorphisms were not associated with response to vinorelbine. No significant difference in toxicity and survival was observed according to SNP genotype.     

甘肃省人群CYP2E1基因多态性与急性白血病易感性的关系

目的 研究甘肃省人群CYP2E1基因多态性和急性白血病易感性的关系.方法 用1∶1配对病例-对照方法,LDR-PCR方法,对甘肃省人群中100例急性白血病患者和100例对照进行CYP2E1基因突变分析.结果 急性白血病组CYP2E1基因C2等位基因频率(13.5%)和CIC2+C2C2基因型频率(22%)均高于对照组(10.5%和19%),但其差异均无统计学意义.进一步分层分析,急性髓系白血病(AML)组C1C2/C2C2基因型频率(27%)高于对照组(19%),其差异无统计学意义.急性淋巴细胞白血病(ALL)组CYP2E1基因C2等位基因频率和C1C2/C2C2基因型频率均与对照组差异无统计学意义(x2=0.446,P=0.504>0.05).结论 甘肃省研究人群CYP2E1基因多态性与急性白血病(AML和ALL)遗传易感性无关.     

CYP2C19 genotype–phenotype discordance in patients with multiple myeloma leads to an acquired loss of drug-metabolising activity

Purpose

Previous reports indicate that discordance between CYP2C19 genotype and enzyme function occurs in up to 37 % of cancer patients with a range of solid tumours. The aim of this study was to determine whether this acquired loss of function in hepatic CYP2C19 activity also occurs in patients with haematological malignancy.

Methods

CYP2C19 genotype was determined in 25 patients with multiple myeloma using PCR–RFLP analysis for the common allelic variants (*2, 681G>A, rs4244285; *3, 636G>A, rs49486893, and *17, ?806C>T, rs12248560). The activity of the enzyme was evaluated using the CYP2C19 probe drug proguanil, and a metabolic ratio used to categorise subjects as extensive or poor metabolisers (PM).

Results

No genotypic PM (homozygous null) were detected in this patient cohort. However, CYP2C19 activity was severely compromised in some multiple myeloma patients, resulting in a PM status in 28 % of subjects. Hence, there was significant (p < 0.0001) discordance between the CYP2C19 activity predicted by genotype and the measured phenotype. Discordant CYP2C19 activity did not correlate with any of the pro-inflammatory markers studied.

Conclusions

Acquired loss of CYP2C19 activity occurs in a substantial proportion of patients with multiple myeloma. This indicates that the previously reported phenomenon is not limited to patients with solid tumours. Thus, measurement of CYP2C19 activity rather than CYP2C19 genotype may be more clinically relevant for the determination of whether loss of CYP2C19 function adversely influences the toxicity and efficacy of certain drugs used in medical oncology.     

Interaction between smoking and CYP2C19*3 polymorphism increased risk of lung cancer in a Chinese population

Cytochrome P450 (CYP) 2C19 is expressed in vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which play a crucial role in either the detoxification or inactivation of potential carcinogens, or the bioactivation of some environmental procarcinogens to reactive DNA-binding metabolites. And smoking is a major risk factor for lung cancer. The purpose of this study is to explore the relationship between the interaction of CYP2C19*3 polymorphism and smoking and lung cancer in a Chinese population. In a Chinese case-control study of lung cancer patients (n?=?420) and healthy controls (n?=?420), we investigated the roles of CYP2C19*3 polymorphism in lung cancer risk using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. We found that the frequency of CYP2C19 ^*3 (AG + AA) genotype was significantly higher in lung cancer patients than that in control subjects (14.28 % versus 4.76 %; P?<?0.001). Multivariable logistic regression analysis showed that after adjustment of other risk factors, the A allele of CYP2C19*3 remains significantly associated with lung cancer. We also found that there was a significant interaction between CYP2C19 ^*3 and smoking in increasing the risk for lung cancer (OR 5.121, 95 % confidence interval [CI] 4.321–10.124; P?=?0.001). The interaction between CYP2C19 ^*3 polymorphism and smoking plays an important role in the mechanism of lung cancer in Chinese population.     

Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies.

PURPOSE: To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype. PATIENTS AND METHODS: We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates. Midazolam was administered intravenously to these patients at least 2 days before docetaxel treatment, and systemic clearances of both drugs were correlated. Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1. RESULTS: Thirty-two patients were enrolled, of whom 31 had full pharmacokinetic data sets. Docetaxel clearance correlated with midazolam clearance, body-surface area, serum albumin, and performance status. Docetaxel and midazolam clearances were normally distributed. In multiple linear regression analyses, midazolam clearance and performance status were the only significant covariates of docetaxel clearance, and the area under the curve of docetaxel, serum levels of alpha-1-acid glycoprotein, and ALT were significant predictors of nadir neutrophil count. No polymorphisms were detected in the 5' regulatory region of CYP3A4. Nine patients of 25 studied were homozygous for the CYP3A5*3 genotype, and had lower mean clearance of midazolam but not docetaxel. The T/T genotype at the C3435T of MDR1, which is associated with reduced P-glycoprotein function, was found in eight of 27 patients. CONCLUSION: Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.     

Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes.

PURPOSE: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. METHODS: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. RESULTS: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. CONCLUSION: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.     

The association of CYP2D6 *10 polymorphism with breast cancer risk and clinico-pathologic characteristics in Chinese women

A relatively little is known of whether CYP2D6 *10 (188 C to T) polymorphism mediates susceptibility to breast cancer. In this study the CYP2D6 *10 polymorphism was detected in Chinese women (286 breast cancer patients and 305 healthy women) by a PCR-RFLP assay. We found that women with the 188T/T genotype displayed a slightly increased risk for breast cancer as compared with those with the 188C/C genotype (OR 1.36, CI 0.89-2.1), the association of the 188T/T genotype with breast cancer risk was more pronounced among postmenopausal women (OR 1.49, CI 0.8-2.76), but the association did not reach statistical significance. Furthermore, we found that patients carrying the 188T/T or T/C genotype were more likely to be a positive lymph node status than those with the 188C/C genotype (OR 2.12, CI 1.08-4.18, P = 0.019). Our results suggest that CYP2D6 *10 mutant 188T/T genotype displays a non-significant increased risk for breast cancer. Moreover, patients carrying 188T/T or T/C genotype might exhibit a more aggressive phenotype than those carrying 188C/C genotype, as the observation association of genotype with clinical outcome may be due to chance, therefore, further studies are required to confirm our present findings.     

Do 5-fluorouracil therapies alter CYP2C19 metaboliser status?

Purpose

To report a case of altered CYP2C19 metaboliser status following 5-fluorouracil treatment.

Methods

A 78-year-old male with stage III colorectal adenocarcinoma was prescribed with weekly iv 5-fluorouracil and folinic acid (FU/FA). Fourteen weeks after starting FU/FA, the patient was enrolled in a clinical study to investigate the role of tumour burden on drug metabolising enzyme activity. CYP2C19 genotype was determined and the activity of CYP2C19 was measured using proguanil (PG) as a probe substrate. A metabolic ratio (PG/CG) for CYP2C19 activity was determined on three separate occasions, 7 days apart.

Results

The patient was homozygous wild type (CYP2C19*1/*1), and on the first test, the metabolic ratio was concordant with the extensive metaboliser genotype. However, at day 14 and day 21, the metabolic capacity of this enzyme had decreased, and the subject had become a poor metaboliser (PG/CG > 30). The patient developed grade III hand and foot syndrome at day 10 of the study during the period of null CYP2C19 activity.

Conclusions

Although 5FU is not a substrate for hepatic drug metabolising CYP enzymes, it may interfere with the synthesis of CYP2C19. Decreased activity of a related enzyme, CYP2C9, following 5FU has been reported previously. Down regulation of CYP2C9 and CYP2C19 synthesis by 5FU therapies may explain the adverse effect of 5FU on the clinical disposition of warfarin and phenytoin.     

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 selectiveestrogen 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 andpolymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Results: Prevalences ofCYP2D6*4, CYP2D6*10 and CYP2C19*2 genotypes were differed significantly (P = 0.01 and P = 0.004) betweenbreast 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 withother reports indicates that drug resistance gene polymorphisms might be indicators of response to tamoxifen therapyin breast cancer cases.     

Effects of the CYP2C19 Genetic Polymorphism on Gastritis,Peptic Ulcer Disease,Peptic Ulcer Bleeding and Gastric Cancer

Background: The CYP2C19 genotype has been found to be an important factor for peptic ulcer healing andH. pylori eradication, influencing the efficacy of proton pump inhibitors (PPIs) and the pathogenesis of gastriccancer. The aim of this study was to investigate clinical correlations of the CYP2C19 genotype in patients withgastritis, peptic ulcer disease (PUD), peptic ulcer bleeding (PUB) and gastric cancer in Thailand. Materialsand Methods: Clinical information, endoscopic findings and H. pylori infection status of patients were assessedbetween May 2012 and November 2014 in Thammasat University Hospital, Thailand. Upper GI endoscopy wasperformed for all patients. Five milliliters of blood were collected for H. pylori serological diagnosis and CYP2C19study. CYP2C19 genotypes were determined by polymerase chain reaction (PCR) and restriction fragment lengthpolymorphism analysis (RFLP) and classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poormetabolizer (PM). Results: A total of 202 patients were enrolled including 114 with gastritis, 36 with PUD, 50 withPUB and 2 with gastric cancer. Prevalence of CYP2C19 genotype was 82/202 (40.6%) in RM, 99/202 (49%) inIM and 21/202 (10.4%) in PM. Overall H. pylori infection was 138/202 patients (68.3%). H. pylori infection wasdemonstrated in 72% in RM genotype, 69.7% in IM genotype and 47.6% in PM genotype. Both gastric cancerpatients had the IM genotype. In PUB patients, the prevalence of genotype RM (56%) was highest followed byIM (32%) and PM(12%). Furthermore, the prevalence of genotype RM in PUB was significantly greater thangastritis patients (56% vs 36%: p=0.016; OR=2.3, 95%CI=1.1-4.7). Conclusions: CYP2C19 genotype IM was themost common genotype whereas genotype RM was the most common in PUB patients. All gastric cancer patientshad genotype IM. The CYP2C19 genotype RM might be play role in development of PUD and PUB. Furtherstudy in different population is necessary to verify clinical usefulness of CYP2C19 genotyping in developmentof these upper GI diseases.     

The T/C polymorphism of the CYP17 gene and G/A polymorphism of the CYP19 gene in endometrial cancer

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. The CYP17 and CYP19 genes encode 17 hydroxylase/17,20-lyase and aromatase, respectively, both involved in sex hormone synthesis. The gene CYP17 and CYP19 are polymorphic and gene variability could contribute to the level of protein biosynthesis. In the present work the distribution of genotypes and frequency of alleles of the C/T polymorphism in promoter region of CYP17 and G/A polymorphism at position Val80 in CYP19 in subjects with endometrial cancer were investigated. Paraffin embedded tumour tissues were obtained from 100 women with endometrial cancer. DNA from normal endometrial tissue (n = 106) served as control. The polymorphisms were determined by PCR-RFLP. The distribution of the genotypes of the C/T polymorphism of CYP17 and G/A polymorphism of CYP19 in both control and patients did not differ significantly (p > 0.05) from those predicted by the Hardy-Weinberg distribution. There were no significant differences (p > 0.05) in genotype distributions and allele frequencies between subgroups assigned to histological stage.The results suggest that C/T polymorphism of the CYP17 gene as well as G/A polymorphism of CYP19 may not be linked with onset and development of endometrial cancer.     

Genetic polymorphisms and cancer risk

While hereditary disease genes have a high lifelong cumulative incidence rate (penetrance), the penetrance for polymorphism genotypes is not high. Polymorphisms relating to cancer incidence are classified into 1. carcinogen metabolizing enzymes (CYPs, GSTs, NQO1, etc.), 2. DNA repair enzymes (OGG1, XRCC1, XPD, etc.), 3. DNA synthesis and methylation (MTHFR, MS, etc.), 4. cytokines and inflammation-related enzymes (IL-1B, TNF-A, MPO, etc.), and 5. sex hormone metabolizing enzymes and the receptors (CYP19, SRD5A2, ER, etc.). Since genotypes cannot be manipulated, they are not the factors subject to prevention. However, the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes (gene-environment interaction), opens the door to genotype applications for disease prevention practice.     

CYP2C19 polymorphisms in patients with gastric and colorectal carcinoma

Background

It has been reported that up to 80% of human cancer arise as a consequence of environmental exposure and host susceptibility factors. Environmental carcinogens are predominantly metabolized by the cytochrome P450 (CYP) superfamily of drug-or xenobiotic-metabolizing enzymes. Genetic variations in these enzymes affect individuals' susceptibility to carcinogens.

Aim of the study

The aim of this study was to evaluate the relationship between CYP2C19 polymorphism and susceptibility to these cancers by means of CYP2C19 genotyping among Turkish subjects.

Methods

DNA of subjects were isolated from leukocytes by high pure template preparation kit (Roche Diagnostics, GmbH, Mannheim, Germany) and genotypes were detected by LightCycler CYP2C19 Mutation Detection Kit by real-time PCR with LightCycler instrument (Roche Diagnostics, cat. no. 3113914).

Results

Being male was associated with a 3.5-fold (OR: 4.27, CI: 2.27–8.05) and 4.27-fold (OR: 3.50, CI: 1.948–6.301) risk for colorectal and gastric carcinoma, respectively. The CYP2C19 ^* 3 heterozygote genotype was not found in either gastric or colorectal carcinoma patients. Although the frequency of CYP2C19^*2 heterozygote genotype is high in patients with gastric and colorectal carcinoma, it is not significantly associated with cancer (OR: 1.79, CI: 0.829–3.865 and OR: 1.998, CI: 0.961–4.154, respectively).

Conclusion

Although the frequency of CYP2C19 ^* 2 heterozygote genotype is high in our patients with gastric and colorectal carcinoma, there is no the relationship between CYP2C19 polymorphism and susceptibility to these cancer.     

Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 are not associated with prognosis,endometrial thickness,or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen

BACKGROUND:

The authors investigated the impact of the genetic polymorphisms cytochrome P450 (CYP) family 2, subfamily D, polypeptide 6, allele *10 (CYP2D6*10) and CYP family 2, subfamily C, polypeptide 19, allele *2,*3 (CYP2C19*2,*3) on disease recurrence in patients with breast cancer who received adjuvant tamoxifen and evaluated the impact of those polymorphisms on endometrial thickness, bone mineral density (BMD), and serum total cholesterol levels.

METHODS:

Patients with primary breast cancer (n=173) who had hormone receptor‐positive tumors and who also received adjuvant tamoxifen were included in the current study. Genetic polymorphisms of CYP2D6*10 and CYP2C19*2,*3 were analyzed.

RESULTS:

Recurrence‐free survival (RFS) rates did not differ significantly between patients with the CYP2D6 *10/*10 genotype (n=40) and patients with the CYP2D6 wild‐type (wt)/wt or wt/*10 genotype (n=133) or between patients with the CYP2C19 *2/*2, *2/*3, or *3/*3 genotypes (n=41) and patients with the CYP2C19 wt/wt, wt/*2, or wt/*3 genotype (n=132). Multivariate analysis indicated that, even after adjustment for well established prognostic factors, these CYP2D6 or CYP2C19 genotypes were not associated significantly with the RFS rate. Moreover, these genotypes did not affect endometrial thickness, BMD, or total cholesterol levels 1 year after the start of tamoxifen treatment.

CONCLUSIONS:

Neither the CYP2D6 *10/*10 genotype nor the CYP2C19 genotype is likely to have a clinically significant impact on prognosis, endometrial thickness, BMD, or total cholesterol levels in Japanese patients with breast cancer who are treated with adjuvant tamoxifen. Cancer 2009. © 2009 American Cancer Society.     

Impact of variable CYP genotypes on breast cancer relapse in patients undergoing adjuvant tamoxifen therapy

Background

Tamoxifen is frequently used for the treatment of hormone receptor positive breast cancer (BC). Mainly CYP2D6 is responsible for the transformation to therapeutically active metabolites, but CYP2C19, CYP2C9 and CYP2B6 also are involved. We investigated the impact of polymorphisms within the genes encoding these CYP enzymes on the relapse-free time (RFT) in patients with BC.

Methods

Ninety-nine patients with hormone receptor positive BC, who had undergone adjuvant tamoxifen therapy, were genotyped for seventeen common variants within the genes encoding CYP2D6, CYP2C9, CYP2C19 and CYP2B6 using TaqMan and PCR-RFLP technology. Kaplan–Meier and Cox regression analyses were performed to elucidate the impact of genetic variants on RFT. Furthermore, CYP2D6 metabolic activity was determined in a subset of 50 patients by assessing dextromethorphan/dextrorphan urinary excretion ratios. CYP2D6 activity was compared to the CYP2D6 allelic combinations to evaluate the predictive value of the CYP2D6 genotyping results on phenotype.

Results

Although a trend toward longer RFTs in carriers of CYP2D6 allele combinations encoding for extensive and ultrafast metabolizer phenotypes was observed, none of the investigated genetic variants had a statistically significant impact on RFT. The combined analysis of five major CYP2D6 variants was useful for the discrimination between poor and non-poor metabolizers.

Conclusions

Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity. Common variants in CYP2C9, CYP2C19, CYP2D6, and CYP2B6 did not have a significant impact on the RFT in this cohort of patients with BC.