Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics.
Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics.
复制标题
单胺氧化酶抑制剂和细胞色素 P450 2D6 状态对 5-甲氧基-N,N-二甲基色胺代谢和药代动力学的影响。
DOI：
10.1016/j.bcp.2010.02.020
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发表时间：
2010
影响因子：
5.8
通讯作者：
Yu,Ai-Ming
中科院分区：
文献类型：
--
作者：
Shen,Hong-Wu;Wu,Chao;Jiang,Xi-Ling;Yu,Ai-Ming
5-甲氧基-N，N-二甲基色胺（5-MeO-DMT）是一种天然的精神活性吲哚烷胺类药物，已被用于娱乐目的。我们前期的研究发现，多态性细胞色素P450 2D 6（CYP 2D 6）催化5-MeO-DMT O-去甲基化生成活性代谢物蟾毒替宁，而5-MeO-DMT主要通过单胺氧化酶（MAO）介导的脱氨基途径失活。因此，本研究旨在研究CYP 2D 6基因型/表型状态和MAO抑制剂（MAOI）对5-MeO-DMT代谢和药代动力学的影响。使用重组CYP 2D 6等位同工酶的酶动力学研究表明，CYP2D6.2和CYP2D6.10表现出2.6倍和40倍的催化效率（Vmax/Km），分别从5-MeO-DMT生产蟾毒替宁，与野生型CYP2D6.1相比。当与MAOI帕吉林共孵育时，10个人肝微粒体中5-MeO-DMT O-去甲基化与丁呋洛尔1′-羟化酶活性（R2=0.98; P<0.0001）和CYP 2D 6含量（R2=0.77; P=0.0007）呈显著强相关，而与其他P450酶活性无明显相关性。此外，在人CYP 2D 6快代谢型肝细胞中，同时MAOI阻断显著减少5-MeO-DMT消耗并增加蟾蜍烯宁形成。在野生型和CYP 2D 6-人源化（Tg-CYP 2D 6）小鼠模型中的体内研究显示，接受相同剂量的5-MeO-DMT（20 mg/kg，i. p.）全身暴露于代谢物蟾毒替宁的比例高出60%。另外，腹腔注射5 mg/kg的肝素钠预处理可明显抑制小鼠的生长。导致对5-MeO-DMT（2 mg/kg，i. p.）的全身暴露增加3.6倍和4.4倍，Tg-CYP 2D 6和野生型小鼠对蟾蜍烯碱的全身暴露量分别高出9.9倍和6.1倍。这些发现表明，MAOI在很大程度上影响5-MeO-DMT代谢和药代动力学，以及由CYP 2D 6介导的蟾蜍烯宁形成。
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibitor (MAOI) on 5-MeO-DMT metabolism and pharmacokinetics. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes showed that CYP2D6.2 and CYP2D6.10 exhibited 2.6- and 40-fold lower catalytic efficiency (Vmax/Km), respectively, in producing bufotenine from 5-MeO-DMT, compared with wild-type CYP2D6.1. When co-incubated with MAOI pargyline, 5-MeO-DMT O-demethylation in 10 human liver microsomes showed significantly strong correlation with bufuralol 1′-hydroxylase activities (R2=0.98; P<0.0001) and CYP2D6 contents (R2=0.77; P=0.0007), whereas no appreciable correlations with enzymatic activities of other P450 enzymes. Furthermore, concurrent MAOI harmaline sharply reduced 5-MeO-DMT depletion and increased bufotenine formation in human CYP2D6 extensive metabolizer hepatocytes. In vivo studies in wild-type and CYP2D6-humanized (Tg-CYP2D6) mouse models showed that Tg-CYP2D6 mice receiving the same dose of 5-MeO-DMT (20mg/kg, i.p.) had 60% higher systemic exposure to metabolite bufotenine. In addition, pretreatment of harmaline (5mg/kg, i.p.) led to 3.6- and 4.4-fold higher systemic exposure to 5-MeO-DMT (2mg/kg, i.p.), and 9.9- and 6.1-fold higher systemic exposure to bufotenine in Tg-CYP2D6 and wild-type mice, respectively. These findings indicate that MAOI largely affects 5-MeO-DMT metabolism and pharmacokinetics, as well as bufotenine formation that is mediated by CYP2D6.