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首页> 外文期刊>Biochemical Pharmacology >Reduced (+/-)-3,4-methylenedioxymethamphetamine ('Ecstasy') metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro.
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Reduced (+/-)-3,4-methylenedioxymethamphetamine ('Ecstasy') metabolism with cytochrome P450 2D6 inhibitors and pharmacogenetic variants in vitro.

机译：在体外使用细胞色素P450 2D6抑制剂和药物遗传学变异体减少（+/-）-3,4-亚甲二氧基甲基苯丙胺（“迷魂药”）代谢。

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摘要

"Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine or MDMA] is a CNS stimulant, whose use is increasing despite evidence of long-term neurotoxicity. In vitro, the majority of MDMA is demethylenated to (+/-)-3,4-dihydroxymethamphetamine (DHMA) by the polymorphic cytochrome P450 2D6 (CYP2D6). We investigated the demethylenation of MDMA and dextromethorphan (DEX), as a comparison drug, in reconstituted microsomes expressing the variant CYP2D6 alleles (*)2, (*)10, and (*)17, all of which have been linked to decreased enzyme activity. With MDMA, intrinsic clearances (V(max)/K(m)) in CYP2D6.2, CYP2D6.17, and CYP2D6.10 were reduced 15-, 13-, and 135-fold, respectively, compared with wild-type CYP2D6.1. With DEX, intrinsic clearances were reduced by 37-, 51-, and 164-fold, respectively. It was evident that CYP2D6.17 displayed substrate-specific changes in drug affinity (K(m)). Compounds potentially used with MDMA [fluoxetine, paroxetine, (-)-cocaine] demonstrated significant inhibition of MDMA metabolism in both human liver and CYP2D6.1-expressing microsomes. These data demonstrate that individuals possessing the CYP2D6(*)2, (*)17, and, particularly, (*)10 alleles may show significantly reduced MDMA metabolism. These individuals, and those taking CYP2D6 inhibitors, may demonstrate altered acute and/or long-term MDMA-related toxicity.
机译：“摇头丸” [（+/-）-3,4-亚甲基二氧基甲基苯丙胺或MDMA]是一种中枢神经系统兴奋剂，尽管有长期的神经毒性证据，其使用量仍在增加。在体外，大多数MDMA通过多态细胞色素P450 2D6（CYP2D6）脱甲基化为（+/-）-3,4-二羟基甲基苯丙胺（DHMA）。我们研究了表达变体CYP2D6等位基因（*）2，（*）10和（*）17的重组微粒体中MDMA和右美沙芬（DEX）作为比较药物的脱甲基作用，所有这些均与降低的酶有关活动。使用MDMA，与野生型CYP2D6相比，CYP2D6.2，CYP2D6.17和CYP2D6.10的固有清除率（V（max）/ K（m））分别降低了15倍，13倍和135倍。 .1。使用DEX，固有间隙分别减少了37倍，51倍和164倍。显然，CYP2D6.17在药物亲和力（K（m））中显示了底物特异性变化。可能与MDMA一起使用的化合物[氟西汀，帕罗西汀，（-）-可卡因]在人肝和CYP2D6.1表达微粒体中均显示出对MDMA代谢的显着抑制作用。这些数据表明拥有CYP2D6（*）2，（*）17，特别是（*）10等位基因的个体可能显示MDMA代谢显着降低。这些个体和服用CYP2D6抑制剂的个体可能表现出急性和/或长期MDMA相关毒性改变。

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