Vevelstad Merete, Øiestad Elisabeth Leere, Bremer Sara, Bogen Inger Lise, Zackrisson Anna-Lena, Arnestad Marianne
Division of Forensic Sciences, Norwegian Institute of Public Health (NIPH), P.O. Box 4404, Nydalen, N-0403 Oslo, Norway.
Division of Forensic Sciences, Norwegian Institute of Public Health (NIPH), P.O. Box 4404, Nydalen, N-0403 Oslo, Norway; School of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, 0316 Oslo, Norway.
Forensic Sci Int. 2016 Apr;261:137-47. doi: 10.1016/j.forsciint.2016.02.027. Epub 2016 Feb 21.
In 2010-2013, 29 fatal intoxications related to the designer drug paramethoxymethamphetamine (PMMA, 4-methoxymethamphetamine) occurred in Norway. The current knowledge about metabolism and toxicity of PMMA in humans is limited. Metabolism by the polymorphic cytochrome P450 (CYP) 2D6 enzyme to the psychoactive metabolite 4-hydroxymethamphetamine (OH-MA), and possibly by additional enzymes, is suggested to be involved in its toxicity. The aim of this work was to study the association between CYP genetics, PMMA metabolism and risk of fatal PMMA toxicity in humans. The frequency distribution of clinically relevant gene variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A5, and the phenotypic blood CYP2D6 metabolic ratio (OH-MA/PMMA) in particular, were compared in fatal PMMA intoxications (n=17) and nonfatal PMMA abuse controls (n=30), using non-abusers (n=305) as references for the expected genotype frequencies in the Norwegian population. Our study demonstrated that the CYP2D6 enzyme and genotype are important in the metabolism of PMMA to OH-MA in humans, but that other enzymes are also involved in this biotransformation. In the fatal PMMA intoxications, the blood concentrations of PMMA were higher and the CYP2D6 metabolic ratios were lower, than in the nonfatal PMMA abuse controls (median (range) 2.1 (0.03-5.0) vs 0.3 (0.1-0.9) mg/L, and ratio 0.6 (0.0-4.6) vs 2.1 (0.2-7.4) p=0.021, respectively). Overall, our findings indicated that, in most cases, PMMA death occurred rapidly and at an early stage of PMMA metabolism, following the ingestion of large and toxic PMMA doses. We could not identify any genetic CYP2D6, CYP2C9, CYP2C19 or CYP3A5 predictive marker on fatal toxicity of PMMA in humans. The overrepresentation of the CYP2D6 poor metabolizer (PM) genotype found in the nonfatal PMMA abuse controls warrants further investigations.
2010年至2013年期间，挪威发生了29起与设计药物对甲氧基甲基苯丙胺（PMMA，4-甲氧基甲基苯丙胺）相关的致命中毒事件。目前关于PMMA在人体内的代谢和毒性的了解有限。据推测，多态性细胞色素P450（CYP）2D6酶将其代谢为具有精神活性的代谢物4-羟基甲基苯丙胺（OH-MA），可能还有其他酶参与其中，这与它的毒性有关。这项研究的目的是探讨CYP基因、PMMA代谢与人类PMMA致命毒性风险之间的关联。比较了致命性PMMA中毒者（n = 17）和非致命性PMMA滥用对照者（n = 30）中CYP2D6、CYP2C9、CYP2C19和CYP3A5临床相关基因变异的频率分布，特别是表型血CYP2D6代谢率（OH-MA/PMMA），以未滥用药物者（n = 305）作为挪威人群预期基因型频率的参考。我们的研究表明，CYP2D6酶和基因型在人类将PMMA代谢为OH-MA的过程中很重要，但其他酶也参与了这种生物转化。在致命性PMMA中毒事件中，PMMA的血药浓度高于非致命性PMMA滥用对照者，CYP2D6代谢率低于非致命性PMMA滥用对照者（中位数（范围）分别为2.1（0.03 - 5.0）对0.3（0.1 - 0.9）mg/L，代谢率为0.6（0.0 - 4.6）对2.1（0.2 - 7.4），p = 0.021）。总体而言，我们的研究结果表明，在大多数情况下，PMMA中毒死亡发生迅速，且在摄入大剂量有毒PMMA后处于PMMA代谢的早期阶段。我们未能确定任何CYP2D6、CYP2C9、CYP2C19或CYP3A5基因预测标志物与人类PMMA致命毒性有关。在非致命性PMMA滥用对照者中发现的CYP2D6慢代谢者（PM）基因型过量现象值得进一步研究。
