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Introducción: Entre las adicciones por drogas, el tabaquismo ocupa el primer lugar como causa de morbimortalidad y es factor de riesgo para seis de las ocho principales causas de muerte en el mundo. La nicotina es el principal componente adictivo del tabaco. En la terapia de reemplazo con nicotina (TRN), la vareniclina y el bupropion son los medicamentos aprobados para tratamiento del tabaquismo, pero los resultados de las clínicas de dejación del tabaquismo sugieren que aún se desconoce muchas variables influyentes en la respuesta al tratamiento. Objetivo: Determinar la adherencia, la tolerabilidad y la efectividad de un programa de dejación de tabaquismo basado en nicotina o bupropion, en pacientes con dependencia al tabaco, seleccionados según los genotipos de las enzimas que metabolizan los dos fármacos. Hallazgos clínicos: Se incluyeron en esta serie 21 fumadores, 67% hombres, con edad promedio de 46,2±11,7 años. Su tabaquismo comenzó a los 17,8±6 años y llevaban fumando 28±13 años. Al inicio del estudio fumaban 17±12 cigarrillos por día (CPD), habían hecho 3,7±2 intentos de dejar de fumar y el puntaje NDSS (escala breve de evaluación de dependencia de la nicotina, por sus siglas en inglés) fue de 22±5 (punto de corte para dependencia a nicotina: 11 o más puntos). Tratamiento: Los pacientes tenían libre acceso telefónico al médico tratante y, cada semana, una consulta consistente en consejería y control del tratamiento farmacológico prescrito según los genotipos CYP2A6 (que codifica la enzima que metaboliza la nicotina) y CYP2B6 (que codifica la enzima que metaboliza el bupropion). Se empleó nicotina en parches transdérmicos de 14 mg el primer mes y luego de 7 mg el segundo mes, complementados con chicles para manejo del síndrome de abstinencia y bupropion en forma de liberación regulada por 300 mg, 1-2 veces al día. Resultados: Después de 8 semanas de tratamiento y 4 de observación, 15 sujetos (71,4%) respondieron en forma parcial/total. El consumo de CPD bajó de 17±12 al inicio del estudio, a 2,2±3,5 al final del estudio, que corresponde a una reducción de 195 cigarrillos/día. Siete de ocho pacientes tratados con bupropion (87,5%) y siete de trece tratados con nicotina (54%) tuvieron respuesta parcial/total. Solo un paciente formulado con nicotina suspendió el medicamento por intolerancia gastrointestinal (náusea y vómito). La tasa de recaídas, evaluada un mes después del tratamiento farmacológico, fue de cero. Se encontró buena correlación genotipo-fenotipo en los individuos tratados con bupropion, pero no en los tratados con nicotina. Relevancia clínica: La inclusión de marcadores farmacogenéticos para la elección de nicotina o bupropion en un programa de dejación de tabaquismo puede mejorar la adherencia, la tolerabilidad al fármaco y la efectividad del tratamiento.
Introduction: Among drug addictions, smoking ranks first as a cause of morbidity and mortality and is a risk factor for six of the eight leading causes of death in the world. Nicotine is the main addictive component of tobacco. In nicotine replacement therapy (NRT), varenicline and bupropion are the approved medications for smoking cessation, but results from smoking cessation clinics suggest that many variables influencing response to treatment remain unknown. Objective: To determine the adherence, tolerability and effectiveness of a smoking cessation program based on nicotine or bupropion, in patients with tobacco dependence, selected according to the genotypes of the enzymes that metabolize the two drugs. Clinical findings: Twenty-one smokers were included in this series, 67% men, with a mean age of 46.2 ± 11.7 years. Their smoking began at 17.8±6 years and they had been smoking for 28±13 years. At baseline, they smoked 17±12 cigarettes per day (CPD), had made 3.7±2 quit attempts, and the NDSS score it was 22±5 (cut-off point for nicotine dependence: 11 or more points). Treatment: The patients had free telephone access to the treating physician and, every week, a consultation consisting of counseling and control of the pharmacological treatment prescribed according to the CYP2A6 genotypes (encoding the enzyme that metabolizes nicotine) and CYP2B6 (coding for the enzyme that metabolizes bupropion). Nicotine was used in transdermal patches of 14 mg the first month and then 7 mg the second month, supplemented with gum to manage the withdrawal syndrome and bupropion in the form of controlled release 300 mg, 1-2 times a day. Results: After 8 weeks of treatment and 4 weeks of observation, 15 subjects (71.4%) responded partially/totally. CPD consumption dropped from 17±12 at the beginning of the study to 2.2±3.5 at the end of the study, which corresponds to a reduction of 195 cigarettes/day. Seven of eight patients treated with bupropion (87.5%) and seven of thirteen treated with nicotine (54%) had a partial/total response. Only one patient receiving nicotine discontinued the medication due to gastrointestinal intolerance (nausea and vomiting). The relapse rate, assessed one month after drug treatment, was zero. Good genotype-phenotype correlation was found in individuals treated with bupropion, but not in those treated with nicotine. Clinical relevance: The inclusion of pharmacogenetic markers for the choice of nicotine or bupropion in a smoking cessation program may improve adherence, drug tolerability, and treatment effectiveness.
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Objective: Tobacco smoke is composed of cancer-causing chemicals referred to as carcinogens. These carcinogens are metabolized by the enzymes of the cytochrome P450 (CYP) family. Our objective was to evaluate the correlation of tobacco consumption parameters with CYP1A1, CYP1B1 and CYP2A6 expression using qRT-PCR in samples of oral squamous cell carcinoma (OSCC). Material and Methods: The sample was divided into 2 groups: Cancer (36 subjects) and non-Cancer (12 subjects). The smokers' participants (36) were evaluated regarding their Nicotine dependence (ND) was assessed by the Fagerström test for cigarette dependence (FTCD). Questions regarding tobacco consumption like the number of cigarettes/day (CPD), duration of use, and pack-years were also evaluated. The Mann-Whitney and Spearman correlation tests were used at a significance level of 5%. Results: 48 participants were included, 32 men (66.7%), 36 smokers (75%) and 27 smokers with OSCC (56.3%). Samples of OSCC expressed more CYP1A1, CYP1B1, and CYP2A6. Especially, the CYP1B1 gene was significantly expressed in OSCC samples, regardless gender or tobacco use. No women expressed CYP2A6, as well as, non-smokers did not express the CYP1A1 and CYP2A6 genes. CYP1A1 gene was higher among men (P = 0.021). Conclusion: Lack of exposure to tobacco may justify the absence of CYP1A1 and CYP2A6 expression in non-smokers. The CYP1B1 gene was significantly expressed in the cancer presence despite gender or tobacco use. The assessment of ND and quantification of tobacco consumption are important instruments in monitoring smokers with benign oral lesions and, especially, in the presence of cancer.(AU)
Objetivo: A fumaça do tabaco é composta de substâncias químicas cancerígenas conhecidas como carcinógenos. Esses carcinógenos são metabolizados pelas enzimas da família do citocromo P450 (CYP). Nosso objetivo foi avaliar a correlação dos parâmetros do consumo de tabaco com a expressão de CYP1A1, CYP1B1 e CYP2A6 por qRT-PCR em amostras de carcinoma de células escamosas bucal (CCEB). Material e Métodos: A amostra foi dividida em 2 grupos: Câncer (36 indivíduos) e sem Câncer (12 indivíduos). Os participantes fumantes (36) foram avaliados quanto à dependência nicotínica (DN) pelo teste de Fagerström para dependência de cigarro (TFDC). Questões relacionadas ao consumo de tabaco como número de cigarros / dia (CPD), tempo de uso e anos-maço também foram avaliadas. Os testes de correlação de Mann-Whitney e Spearman foram utilizados com nível de significância de 5%. Resultados: foram incluídos 48 participantes, 32 homens (66,7%), 36 fumantes (75%) e 27 fumantes com CCEB (56,3%). Amostras de CCEB expressaram mais CYP1A1, CYP1B1 e CYP2A6. Especialmente, o gene CYP1B1 foi significativamente expresso em amostras de CCEB, apesar do sexo ou uso de tabaco. Nenhuma mulher expressou CYP2A6, assim como, não fumantes não expressaram os genes CYP1A1 e CYP2A6. O gene CYP1A1 foi maior entre os homens (P = 0,021). Conclusão: A falta de exposição pode justificar a ausência da expressão dos genes CYP1A1 e CYP2A6 entre não fumantes. O gene CYP1B1 foi significativamente expresso na presença de câncer, independentemente do sexo ou do uso de tabaco. A avaliação da DN e a quantificação do consumo de tabaco são importantes instrumentos no acompanhamento de fumantes com lesões bucais benignas e, principalmente, na presença de câncer (AU)
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Humans , Tobacco Use Disorder , Carcinoma , Carcinoma, Squamous Cell , Cytochrome P-450 CYP1A1 , Cytochrome P-450 CYP1B1 , Cytochrome P-450 CYP2A6ABSTRACT
Objective:Oral fluoropyrimidine S-1 contains tegafur,gimeracil,and oteracil;among them,tegafur is the major active pre-cursor,which is metabolized to 5-fluorouracil by cytochrome P4502A6(CYP2A6).We examined the associations between CYP2A6 poly-morphisms and the treatment outcomes of adjuvant S-1 in patients with gastric cancer.Methods:Two hundred patients diagnosed with pathological stageⅡ-Ⅲgastric cancer were included in this study,and they received adjuvant S-1(40 mg/m2,bid,days 1-28,ev-ery 6 weeks for eight cycles)after curative surgery.Additionally,we analyzed the wild-type allele(W)(CYP2A6*1)and four variant al-leles(V)(CYP2A6*4,*7,*9,and*10).Results:Two hundred patients were enrolled in this study between November 2007 and July 2013.With a median follow-up of 46.4 months(range:12.5-80.1),the 3-year relapse-free survival(RFS)and overall survival(OS)rates were 83.1%(95% confidence interval(CI),77.7%-88.5%)and 94.8%(95% CI,91.6%-98.0%),respectively.However,RFS differed signifi cantly according to the CYP2A6 genotype.The 3-year RFS rates were 95.9% for W/W,83.1% for W/V,and 72.5% for V/V(P=0.032)gen-otypes.Grades 3 and 4 overall toxicity did not differ according to genotype for any grade(P=0.628 and P=0.227,respectively).Conclu-sions:CYP2A6 genotypes correlate with the outcome of S-1 chemotherapy,wherein patients with the variant genotypes show worse prognosis.Additionally,polymorphism detection may be used as a biomarker to guide clinical chemotherapy choices for adjuvant ad-ministration of gastric cancer therapy.
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Objective: In this study, a simple and reliable high performance liquid chromatographic method with UV detection was developed and validated for rapid determination of coumarin hydroxylase activity in rat hepatic microsomes. Materials and Methods: The chromatographic separation was achieved using Zorbax Eclipse XDB C18 column (150×4.6 mm, 5 μm), which was kept at 40°C. The isocratic mobile phase consisted of methanol and 1% glacial acetic acid mixture (35:65, v/v) with a flow rate of 0.6 ml/min. The effluent was monitored at 320 nm using photodiode array detector (PDA). 6-hydroxychlorzoxazone (6-OH CZX) was used as internal standard. Results and Conclusion: The method exhibited good linearity (R2 >0.999) for both coumarin (COUM) and its 7-hydroxy metabolite (7-OH COUM) over the assayed concentration range (0.025-5.0 μM) and demonstrated good intra-day and inter-day precision and accuracy (relative standard deviations and the deviation from predicted values were less than 15%). The detection limits were 0.001 and 0.005 μM for coumarin and 7- hydroxycoumarin, respectively. This method was also successfully applied for studying the effect of three phytochemicals on hepatic CYP2A6 activity in rats.
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In the cytochrome P450 superfamily, the murine hepatic cytochrome P450 2A5 (CYP2A5) and its human orthologue CYP2A6 catalyze the metabolism of various endogenous and exogenous compounds including steroid hormone, bilirubin and procarcinogens such as nitrosamines and aflatoxin B1. Genetic polymorphism of CYP2A6 can result in the individual differences of xenobiotic metabolism. Unlike the most other CYPs, CYP2A5/CYP2A6 are induced under pathological conditions of liver injury induced by xenobiotics, hepatitis and liver neoplasm. This article provides an overview of the structures, distribution and biological characteristics of CYP2A5/CYP2A6 and subsequently summarizes their gene regulation mechanisms.
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Background: Genetic and metabolic factors associated with nicotine metabolism may be related to smoking behavior. Aim: To assess the prevalence of allelic and genotype variants of CYP2A6 in a sample of Chilean subjects and to evaluate their relationship with smoking and tobacco dependence. Material and Methods: The genotype frequencies for *2, *3 and *4 of CYP2A6*1 (wild type) gene were determined by polymerase chain reaction (PCR) in 54 volunteers. Addiction to tobacco was evaluated using the Fagerstrom Test. The association between the presence of allelic variants of CYP2A6 and smoking and tobacco dependence was evaluated with chi square test. Results: The prevalence of *1, *2 (wt/*2), *3 (wt/*3 or *31*3) and *4 (del/del) were 92.6%, 3.7%, 0% y 3.7%, respectively. No significant association was observed between being a carrier of a variant genotype of CYP2A6 and smoking or tobacco dependence. Conclusions: In this sample of Chilean individuals we did not find a relation between any CYP2A6 genotype with smoking or tobacco dependence.
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Aryl Hydrocarbon Hydroxylases/genetics , Polymorphism, Genetic/genetics , Smoking/genetics , Tobacco Use Disorder/genetics , DNA , Alleles , Gene Frequency , Genetic Predisposition to Disease/genetics , Genotype , Pilot Projects , Polymerase Chain Reaction , PrevalenceABSTRACT
El desarrollo de la dependencia por la nicotina está determinado no solamente por factores sociales, sino además por factores psicológicos y biológicos individuales. Ha sido demostrado que el citocromo P450 2A6 (CYP2A6) humano, la enzima que cataliza el metabolismo de la nicotina, presenta gran variabilidad interindividual e interétnica en los niveles de expresión y actividad. La variación interindividual en la actividad metabólica puede afectar el metabolismo de los sustratos de CYP2A6 incluyendo la nicotina, cotinina (el mayor metabolito de la nicotina), diferentes procancerígenos tabaco-específicos, cumarina y muchas toxinas. La presente revisión analiza la literatura científica relacionada con las variaciones en CYP2A6 y el consumo de tabaco.
The development of nicotine dependence is determined not only by social factors but also by individual psychological and biological factors. Human cytochrome P450 2A6 (CYP2A6), the enzyme that catalyses the metabolism of nicotine, has been shown to have large interindividual and interethnic variability in expression and activity levels. The interindividual variation in metabolic activity may affect the metabolism of CYP2A6 substrates including nicotine, cotinine (the major metabolite of nicotine), several tobaccospecific procarcinogens, coumarin and many toxins. The present review analyses the scientific literature related to variations in CYP2A6 and tobacco consumption.
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AIM To identify potential amino acid residues that contribute to different catalytic characteristics of CYP2A6 and CYP2A13 enzymes in nicotine metabolism. METHODSWild type of CYP2A6 and CYP2A13 and their mutants CYP2A6V117A, CYP2A6G164H, CYP2A6I208S, CYP2A6R372H, CYP2A6S465P and CYP2A13A117V, CYP2A13H164G, CYP2A13S208I, CYP2A13H372A and CYP2A13P465S, were subjected kinetic analysis in nicotine 5'-hydroxylation. RESULTS For CYP2A6, substitution of isoleucine 208 to serine caused dramatic kinetic property changes with K_m and V_( max) varied from 62.25 μmol·L~(-1) and 6.53 mol·min~(-1)·moL~(-1) to 345 μmol·L~(-1) and 2.19 mol·min~(-1)·moL~(-1). However, the corresponding serine 208 to isoleucine mutation did not heavily affect the enzyme activity in CYP2A13. The histidine 372 to arginine mutation resulted in a remarkable catalytic efficiency decrease with K_m and V_( max) changes from 26.01 μmol·L~(-1) and 24.51 mol·min~(-1)·moL~(-1) to 148.7 μmol·L~(-1) and 6.11 mol·min~(-1)·moL~(-1) in CYP2A13, but the switching of argenine 372 to histidine did not show expected corresponding crucial influence in CYP2A6 activity. Substitutions on the other positions changed enzyme activities in different rates. CONCLUSION The isoleucine 208 is crucial to human CYP2A6, while the 372 histidine is a key amino acid residue for CYP2A13 in nicotine 5'-hydroxylation.
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Objective To investigate the relationships between genetic polymorphism of CYP2A6 alone or in combination with smoking and hereditary susceptibility to bladder cancer.Methods Based on case-control study,CYP2A6*4 was determined by the nested polymerase chianreaction(nPCR)in 186 patients with bladder cancer and 192 nontumorous controls.The relations between the genetypes of CYP2A6*4 alone or combinated with smoking and bladder cancer was estimated with the X2 test and logistic regression model.Results In the case subjects,the number of the wil/wil genetype was 168,the number of the wil/del genetype was 13,and the number of the del/del genetype was 5.In the control subjects,the number of the wil/wil genetype was 150,the number of the wil/del genetype was 32,and the number of the del/del genetype was 10.The frequency of CYP2A6 del allele was significantly lower in the case Subjects(9.68%)than the controls(21.88%,P＜0.05,OR:0.383).When eombinated with smoking,the risk of bladder cancer in smokers was significantly higher than nonsmoker(P＜0.05,OR=2.322).In smokers,the frequency of CYP2A6 del allele was significantly lower in cases(7.88%)than controls(28.00%,P＜0.05,OR=0.221).In smoking people,the one with CYP2A6 del genotype had a lower risk of bladder cancer than the one with CYP2A6 wild genotype(OR=0.221,95%CI:0.092,0.534).Conclusions Genetic polymorphisms of CYP2A6 are associated with the susceptibility to bladder cancer and have interaction with smoking in carcinogenesis of bladder cancer.Deficient CYP2A6 activity to genetic polymorphism mayreduee bladder cancer risk in smokers.
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CYP2A6 is an important drug metabolic enzyme that plays a central role in pharmacology and toxicology.Coumarin and nicodine are mainly metabolized by it.CYP2A6 also have a close connection with diseases that related to smoking.While hnRNP A1 is a protein that shows an important regulative action on some specific genes at post-transcription level.Recently,researchers are paying more and more attention to the relationship between the activity of CYP2A6 and the expression of hnRNPA1.In order to master the change rule of CYP2A6 activity,we try to explain the regulative effect on CYP2A6 by hnRNP A1 at post-transcription level,which will bring an important effect on guiding clinical medicine treatments and smoking addictive therapy.
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<p><b>OBJECTIVES</b>To elucidate the association between genetic polymorphisms ofCYP2a6 andCYP2E1 and urothelial cancer susceptibility.</p><p><b>METHODS</b>A total of 137 Japanese patients with urothelial cancer and 217 Japanese healthy controls, frequency-matched for age and gender, were selected. The polymorphisms ofCYP2A6 andCYP2E1 were analyzed by PCR-RFLP, and cigarette smoking histories were obtained through interviews</p><p><b>RESULTS</b>The frequency ofCYP2A6 homozygote deletion genotype was 2.9% in the patients, compared with 3.2% in the controls (OR=0.84, 95% CI 0.24-2.96). The frequencies ofCYP2E1 C1/c2 andC2/c2 were 27.7% and 4.4% in the patients, compared with 35.5% and 6.0% in the controls (OR=0.68, 95% CI 0.42-1.09, OR=0.67, 95% CI 0.24-1.84, respectively). No statistically significant differences were observed when theCYP2A6 homozygote deletion genotype and theCYP2E1 genotypes were examined relative to smoking status.</p><p><b>CONCLUSIONS</b>Our data indicate that neither a relationship between genetically impaired nitrosamine metabolism and tobacco-smoking consumption, nor urothelial cancer risk related to theCYP2A6 deletion genotype andCYP2E1 Rsa I genotype was found in Japanese population.</p>
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Objectives: To elucidate the association between genetic polymorphisms of CYP2A6 and CYP2E1 and urothelial cancer susceptibility. Methods: A total of 137 Japanese patients with urothelial cancer and 217 Japanese healthy controls, frequency-matched for age and gender, were selected. The polymorphisms of CYP2A6 and CYP2E1 were analyzed by PCR-RFLP, and cigarette smoking histories were obtained through interviews. Results: The frequency of CYP2A6 homozygote deletion genotype was 2.9% in the patients, compared with 3.2% in the controls (OR=0.84, 95% CI 0.24−2.96). The frequencies of CYP2E1 C1/c2 and C2/c2 were 27.7% and 4.4% in the patients, compared with 35.5% and 6.0% in the controls (OR=0.68, 95% CI 0.42 −1.09, OR=0.67, 95% CI 0.24−1.84, respectively). No statistically significant differences were observed when the CYP2A6 homozygote deletion genotype and the CYP2E1 genotypes were examined relative to smoking status. Conclusions: Our data indicate that neither a relationship between genetically impaired nitrosamine metabolism and tobacco-smoking consumption, nor urothelial cancer risk related to the CYP2A6 deletion genotype and CYP2E1 Rsa I genotype was found in Japanese population.
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Cytochrome P-450 CYP2E1 , Genotype , NeoplasmsABSTRACT
Objective To investigate the correlation between the alleles polymorphism of CYP2A6 and CYP2B6 and blood concentration of Valproate sodium(VPA).Methods The 165 epilepsy patients received simplex VPA and without dysfunction of liver and kidney were chose in this study.The alleles polymorphism of CYP2A6 in 95 cases and CYP2B6 in 70 cases were detected by polymerase chain reaction(PCR).Fluorescence polarization immunoassay(FPIA) was used to measure the blood concentration of VPA.Results The frequence of allele CYP2A6*4 in 95 cases was 13.2%.The blood concentration of VPA in patients with allele CYP2A6*4[(4.23?0.27)mg/ml]was significantly higher than that in patients without allele CYP2A6*4[(3.35?0.38)mg/ml](P