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首页> 外文OA文献 >Exploring the role of mu opioid receptor (OPRM1) and CYP2B6 gene variations for methadone pharmacogenomics : can these variations be used to advance toxicological interpretation post-mortem?
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Exploring the role of mu opioid receptor (OPRM1) and CYP2B6 gene variations for methadone pharmacogenomics : can these variations be used to advance toxicological interpretation post-mortem?

机译：探讨mu阿片受体（OpRm1）和CYp2B6基因变异在美沙酮药物基因组学中的作用：这些变异可用于推进死后的毒理学解释吗？

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摘要

Methadone is increasingly involved in drug overdose cases and the molecular actions of the drug in vivo are largely unknown requiring elucidation. This study set out to examine the relationship between methadone toxicity and CYP2B6 and mu (μ) opioid receptor (OPRM1) single nucleotide polymorphisms (SNPs). Using SNP genotyping, the association between OPRM1 A118G and CYP2B6 T750C, G516T, and A785G variations and post-mortem methadone concentrations were investigated. The allele frequencies of OPRM1 and CYP2B6 variants were then studied in a control population of live non-methadone using subjects, to determine the prevalence and distribution of specific variations in post-mortem and living subjects. Further in vitro study was conducted to assist in interpreting the association between OPRM1 and CYP2B6 variations and individual susceptibility to methadone. Cloning strategies were designed for the studies of promoter activities affected by the T750C promoter SNP on CYP2B6 expression, and the role of the OPRM1 A118G variation for receptor internalisation following methadone treatment was investigated. A significant association was identified between high post-mortem methadone concentrations and G561T and A785G (CYP2B6*6) variations reflecting poor methadone metabolism. Furthermore, the OPRM1 A118G SNP significantly correlated with higher post-mortem methadone concentrations and the in vitro analysis of A118G indicated that this could be due to a reduction in receptor internalisation in 118 AG subjects. The findings from the research contribute to pre-determining, in part, individual susceptibility to methadone accumulation and toxicity. Specific screening to identify CYP2B6*6 and OPRM1 A118G carriers prior to addiction treatment could therefore be valuable as part of a cost-effective risk management strategy. Furthermore, CYP2B6*6 and A118G could be used to interpret toxicology results identifying subjects with poor metabolism.
机译：美沙酮越来越多地与药物过量有关，并且尚不清楚药物在体内的分子作用，需要阐明。本研究着手研究美沙酮毒性与CYP2B6和mu（μ）阿片受体（OPRM1）单核苷酸多态性（SNPs）之间的关系。使用SNP基因分型，研究了OPRM1 A118G和CYP2B6 T750C，G516T和A785G变异与验尸美沙酮浓度之间的关联。然后使用受试者在对照组非活美沙酮中研究OPRM1和CYP2B6变体的等位基因频率，以确定死后和活受试者中特定变异的普遍性和分布。进行了进一步的体外研究，以帮助解释OPRM1和CYP2B6变异与个体对美沙酮的敏感性之间的关联。设计了克隆策略，用于研究受T750C启动子SNP影响的CYP2B6表达的启动子活性，并研究了美沙酮治疗后OPRM1 A118G变异体对受体内在化的作用。死后高的美沙酮浓度与反映美沙酮代谢不良的G561T和A785G（CYP2B6 * 6）变异之间存在显着相关性。此外，OPRM1 A118G SNP与更高的死后美沙酮浓度显着相关，A118G的体外分析表明，这可能是由于118名AG受试者体内受体内在化的降低。该研究的发现部分有助于预先确定个人对美沙酮蓄积和毒性的敏感性。因此，在成瘾治疗之前进行特异性筛查以识别CYP2B6 * 6和OPRM1 A118G携带者可能是具有成本效益的风险管理策略的一部分。此外，CYP2B6 * 6和A118G可用于解释毒理学结果，从而确定代谢不良的受试者。

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    Bunten Hannah;

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  • 年度 2010
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