The Association Between Epoxide Hydrolase Genetic Variant and Effectiveness of Nicotine Replacement Therapy in a Han Chinese Population

Abstract

Nicotine is a psychoactive alkaloid that is thought to play a key role in addiction to commercial tobacco products [1] and cotinine is its primary metabolite [2]. Pharmacological treatment, such as nicotine replacement therapy (NRT), is a valid solution to this problem. Tobacco smoke contains many carcinogens such as nitrosamines [i.e., nicotinederived nitrosamine ketone (NNK) and N-nitrosonornicotine (NNN)], and nicotine undergoes chemical conversion into NNK and NNN during the processes of curing and smoking [3]. Microsomal epoxide hydrolase (EPHX) is responsible for the metabolism of polycyclic aromatic hydrocarbons and the detoxification of pro-carcinogens in the process of smoking [4]. Therefore, in this study we aimed to investigate whether the genetic polymorphisms of EPHX, rs1051740 and rs2234922, are associated with the metabolic processing of cotinine in nicotine abstinence and craving.Two hundred and eleven eligible participants took part in this study, and were randomly divided into active or placebo treatment groups in a double-blind manner (see Supplementary Materials). There were no significant demographic differences between the sublingual nicotine tablet and placebo groups except for age (Table S1). The distributions of the genotypes of the two loci did not significantly differ between the two groups. The genotypes of the participants deviated from Hardy-Weinberg equilibrium for both polymorphisms (P \ 0.01 for rs1051740 and P = 0.01 for rs2234922).One-way ANOVA was used between the genotypes with the 2 loci, and age was a covariate (rs1051740 P \ 0.05 and rs2234922 P [ 0.05) (Table S2). There was an interaction between age and genotype (F = 3.90, df = 2, P = 0.02) for rs1051740. The interaction of time, grouping (placebo/NRT), and genotype was significantly associated with the difference between the urinary cotinine concentration at the end of the 2nd month and baseline (F = 5.20, P = 0.01); the TT genotype was significantly associated with the interaction of time and grouping (F = 14.12, P \ 0.01) for rs1051740. In rs1051740, the interaction of time, grouping, and genotype was significantly associated with the difference between the urinary cotinine concentration at the end of the 3rd month and baseline (F = 4.33, P = 0.01); and the TT genotype was significantly associated with the interaction of time and grouping (F = 28.23, Fan Wang and Yanlong Liu have contributed equally to this work. Electronic supplementary materialThe online version of this article

Drug addiction: a curable mental disorder?

“…The long-lasting neuroplasticity changes induced by exposure to drugs of abuse are mediated by specific gene transcriptions [97]. Genetic analysis and functional studies have identified a wide range of candidate genes and their variants that regulate drug addiction, e.g., dopamine-related genes, glutamate-related genes, and transcription factors (e.g., the immediate early gene fosB) [97][98][99]. It has been shown that the development of addiction is positively associated with genetic factors, suggesting a high heritability feature of addiction [100].…”

Special Topic on Mental Health and Addiction

“…Wang et al [11] found that two singlenucleotide polymorphisms of microsomal epoxide hydrolase (rs1051740 and rs2234922) are involved in the processes of nicotine metabolism and abstinence. In addition, both polymorphisms are associated with the effectiveness of nicotine replacement therapy in a Chinese population.…”