Aly Sanaa M, Hakim Florian, Richeval Camille, Hennart Benjamin, Gaulier Jean-Michel, Allorge Delphine
Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
CHU Lille, Service de Toxicologie-Génopathies, Lille, 59037, France.
Int J Legal Med. 2023 Sep;137(5):1431-1437. doi: 10.1007/s00414-023-03052-8. Epub 2023 Jul 17.
Tramadol (TR) metabolism is performed by polymorphic enzymes that are influenced by genetic polymorphisms. Within this scope, the study presented here aimed to describe 41 genetic variants within CYP2D6, CYP2B6, and CYP3A4 genes in 48 cases of TR-related death that may be involved in the response to TR and to assess whether there is a correlation between these genetic variants and metabolic ratios (MRs). Blood samples from 48 victims of a TR-related death were analyzed to determine the concentrations of TR and its metabolites [O-desmethyltramadol (M1) & N-desmethyltramadol (M2)] using a LC-MS/MS method. All the samples were also genotyped for 41 common CYP2D6, CYP2B6, and CYP3A4 single nucleotide polymorphisms (SNPs) using the HaloPlex Target Enrichment system. Cases with the T/- genotype (rs35742686 in CYP2D6) had significantly higher M2/M1 ratio than cases with T/T genotype and cases with the G/A genotype (rs35599367 in CYP3A4) had significantly higher MR2 (TR/M2) ratio than cases with G/G genotype. The frequency of tested SNPs which belong to CYP2D6, CYP2B6, and CYP3A4 revealed the over-presentation of 2 SNPs (rs1058172 in CYP2D6 and rs4803419 in CYP2B6) in TR overdose group, which could have toxicological implications. These results indicate these polymorphisms in CYP2D6, CYP2B6, and CYP3A4 might influence the function and could increase the risk of toxicity. However, these findings should be supported in future studies with larger groups of cases.
曲马多（TR）的代谢由受基因多态性影响的多态性酶进行。在此范围内，本研究旨在描述48例TR相关死亡病例中细胞色素P450 2D6（CYP2D6）、细胞色素P450 2B6（CYP2B6）和细胞色素P450 3A4（CYP3A4）基因内的41个基因变异，这些变异可能与对TR的反应有关，并评估这些基因变异与代谢率（MRs）之间是否存在相关性。采用液相色谱-串联质谱（LC-MS/MS）法分析了48例TR相关死亡受害者的血样，以测定TR及其代谢物[O-去甲基曲马多（M1）和N-去甲基曲马多（M2）]的浓度。还使用HaloPlex靶向富集系统对所有样本进行了41种常见的CYP2D6、CYP2B6和CYP3A4单核苷酸多态性（SNP）基因分型。T/-基因型（CYP2D6中的rs35742686）的病例M2/M1比值显著高于T/T基因型的病例，G/A基因型（CYP3A4中的rs35599367）的病例MR2（TR/M2）比值显著高于G/G基因型的病例。属于CYP2D6、CYP2B6和CYP3A4的检测SNP频率显示，TR过量组中2个SNP（CYP2D6中的rs1058172和CYP2B6中的rs4803419）出现频率过高，这可能具有毒理学意义。这些结果表明，CYP2D6、CYP2B6和CYP3A4中的这些多态性可能影响其功能，并可能增加毒性风险。然而，这些发现应在未来更大病例组的研究中得到证实。
