Division of Mental Health & Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
Pharmacogenomics. 2011 Oct;12(10):1397-406. doi: 10.2217/pgs.11.103. Epub 2011 Sep 8.
Methadone maintenance therapy is one of the standard treatments for heroin addiction. The isozyme CYP3A4 of the CYP system is one of the metabolic enzymes, as well as CYP2B6, responsible for the metabolism of methadone. The aim of the present study is to evaluate the potential use of genetic polymorphisms in CYP3A4 as biomarkers for the prediction of methadone treatment responses.
MATERIALS & METHODS: A total of 366 Han Chinese methadone maintenance treatment patients in Taiwan were recruited in this study. Main clinical assessments included the clinical opioid withdrawal scale (COWS), the treatment emergent symptom scale (TESS) and the plasma concentrations of methadone and its metabolites. Genetic associations of six SNPs in the CYP3A4 gene were calculated using a general linear model.
Genotypes and allele types of rs4646440 and rs2242480 were found to be significantly associated with the severity of withdrawal symptoms rated by COWS (p = 0.012, 0.0096, 0.017 and 0.012, respectively) as well as the side effects rated by TESS (p = 0.0089, 0.028, 0.0027 and 0.0085, respectively). The allele types associated with more severe withdrawal symptoms are also associated with more severe side effects and less betel nut (Areca catechu) use (p = 0.009 for rs4646440, p = 0.0063 for rs2242480). Further analyses on specific withdrawal symptoms in COWS showed that the genetic variants in rs4646440 are significantly associated with heart rate (allele type p = 0.0019).
These results suggested that genetic variants in the CYP3A4 gene may be useful indicators for the severity of side effects and withdrawal symptoms for methadone treatment.
美沙酮维持治疗是海洛因成瘾的标准治疗方法之一。CYP 系统的同工酶 CYP3A4 是代谢酶之一，CYP2B6 也负责美沙酮的代谢。本研究旨在评估 CYP3A4 基因遗传多态性作为预测美沙酮治疗反应的生物标志物的潜力。
本研究共招募了 366 名台湾汉族美沙酮维持治疗患者。主要临床评估包括临床阿片类药物戒断量表（COWS）、治疗中出现的症状量表（TESS）和血浆中美沙酮及其代谢物的浓度。使用一般线性模型计算 CYP3A4 基因中 6 个 SNP 的遗传关联。
发现 rs4646440 和 rs2242480 的基因型和等位基因类型与 COWS 评定的戒断症状严重程度（p = 0.012、0.0096、0.017 和 0.012）以及 TESS 评定的副作用严重程度（p = 0.0089、0.028、0.0027 和 0.0085）显著相关。与更严重戒断症状相关的等位基因类型也与更严重的副作用和更少的嚼槟榔（Areca catechu）使用相关（rs4646440 为 p = 0.009，rs2242480 为 p = 0.0063）。在 COWS 中对特定戒断症状的进一步分析表明，rs4646440 中的遗传变异与心率显著相关（等位基因类型 p = 0.0019）。
这些结果表明，CYP3A4 基因中的遗传变异可能是美沙酮治疗中副作用和戒断症状严重程度的有用指标。
