Center for Human Identification, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA.
Department of Forensic Medicine, University of Helsinki, P.O Box 40, 00014, Helsinki, Finland.
Pharmacogenomics J. 2020 Feb;20(1):94-103. doi: 10.1038/s41397-019-0088-y. Epub 2019 Apr 11.
Phase I tramadol metabolism requires cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) to form O-desmethyltramadol (M1). CYP2D6 genetic variants may infer metabolizer phenotype; however, drug ADME (absorption, distribution, metabolism, and excretion) and response depend on protein pathway(s), not CYP2D6 alone. There is a paucity of data regarding the contribution of trans-acting proteins to idiosyncratic phenotypes following drug exposure. A genome-wide association study identified five markers (rs79983226/kgp11274252, rs9384825, rs62435418/kgp10370907, rs72732317/kgp3743668, and rs184199168/exm1592932) associated with the conversion of tramadol to M1 (M1:T). These SNPs reside within five genes previously implicated with adverse reactions. Analysis of accompanying toxicological meta-data revealed a significant positive linear relationship between M1:T and degree of sample polypharmacy. Taken together, these data identify candidate loci for potential clinical inferences of phenotype following exposure to tramadol and highlight sample polypharmacy as a possible diagnostic covariate in post-mortem genetic studies.
I 期曲马多代谢需要细胞色素 P450 家族 2，亚家族 D，多肽 6（CYP2D6）形成 O-去甲曲马多（M1）。CYP2D6 遗传变异可能推断代谢表型；然而，药物 ADME（吸收、分布、代谢和排泄）和反应取决于蛋白质途径，而不仅仅是 CYP2D6。关于在药物暴露后，反式作用蛋白对个体表型的贡献的数据很少。全基因组关联研究确定了五个标记（rs79983226/kgp11274252、rs9384825、rs62435418/kgp10370907、rs72732317/kgp3743668 和 rs184199168/exm1592932）与曲马多转化为 M1（M1:T）有关。这些 SNP 位于先前与不良反应相关的五个基因内。对伴随的毒理学元数据的分析显示，M1:T 与样本多药治疗的程度之间存在显著的正线性关系。综上所述，这些数据确定了曲马多暴露后潜在临床表型推断的候选基因座，并强调了样本多药治疗作为死后遗传研究中可能的诊断协变量。
