Sigara Bağımlılığında Nikotinik Kolinerjik Reseptörler ve Cyp2a6, Cyp2b6, İlaç Taşıyıcı Proteini Mdr1, Nöronal Nitrik Oksit Sentaz Genetik Polimorfizmlerinin Etkileri

Abstract

Smoking causes health problems. Yet, cigarette use is common because of nicotine in cigarettes which causes dependence. Currently, nicotine itself, bupropion and varenicline are used in smoking cessation therapies. Although drug therapy increases the chance of smoking cessation as compared to interventions without drugs, cessation rates are still low. Pharmacogenomic optimization of smoking cessation therapies may increase success rates. Nicotine acts on nicotinic cholinergic receptors. CYP2A6 metabolizes nicotine first to cotinine and than to trans-3'-hydroxycotinine. CYP2B6 contributes to metabolism. MDR1 is an efflux protein which is widely expressed in the central nervous system. Neuronal nitric oxide synthase is responsible for the synthesis of nitric oxide which is a neurotransmitter in the central nervous system. Our aim in this study is to investigate the effects of CHRNA3 rs578776, CHRNA4 rs1044396-rs1044397, CHRNA5 rs16969968, CYP2A6*1A, *1B, *4, *9, CYP2B6 rs2279343, MDR1 rs1128503-rs2032582-rs1045642, nNOS exon 18 and exon 29 polymorphisms on nicotine dependence and smoking therapy outcomes. 130 smokers who applied to a clinic for smoking cessation and 130 non-smokers were recruited. The severity of nicotine dependence in smokers was determined by the Fagerström test for nicotine dependence. 70 smokers were highly nicotine dependent, whereas 60 were moderately or low dependent. For smoking cessation, 40 smokers used nicotine replacement therapy, while 47 used bupropion, 15 used bupropion plus nicotine replacement therapy and 28 used varenicline. After 12 weeks of treatment, the subjects were re-contacted for asking if they were able to quit smoking or not. Genotyping was performed by a polymerase chain reaction and restriction analysis. Nicotine metabolite ratios were determined by using liquid chromatography. AA genotype of CHRNA4 rs1044396 (p=0.02), A allele of CHRNA5 rs16969968 (p=0.003), T allele of MDR1 rs1128503 (p=0.01), T/A allele of MDR1 rs2032582 (p=0.018) and MDR1 TT-TT-TT haplotype (p= 0.047) were found to be associated with moderate or low dependency. There was an association between T allele of CHRNA3 rs578776 and low cessation rates of bupropion plus NRT treatment (p=0.033). In addition, TT genotype of nNOS exon 29 polymorphism was associated with higher cessation rates in bupropion treatment (p=0.034). According to these findings; CHRNA3 rs578776, CHRNA4 rs1044396, CHRNA5 rs16969968, MDR1 rs1128503, MDR1 rs2032582, nNOS exon 29 polymorphisms may contribute to pharmacogenomic optimization of nicotine dependence treatment as new biomarkers in the Turkish population.