CYP450-Mediated Metabolism of Mitragynine and Investigation of Metabolites in Human Urine
CYP450-Mediated Metabolism of Mitragynine and Investigation of Metabolites in Human Urine
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DOI：
10.1093/jat/bkz108
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发表时间：
2020-05-01
影响因子：
2.5
通讯作者：
Kerrigan, Sarah
中科院分区：
文献类型：
--
作者：
Basiliere, Stephanie;Kerrigan, Sarah
Mitragyna speciosa（Kratom）已经成为一种娱乐性药物和药物阴谋的物质。虽然该药物最初用于娱乐性镇静和欣快作用，但最近其使用与阿片类戒断综合征的非医学监督治疗有关。Mitragynine是kratom中的主要生物碱。虽然已经鉴定了mitragynine的代谢产物，但负责其生物转化的细胞色素P450（CYP 450）酶仍在研究中。本研究的目的是进一步了解与mitragynine相关的CYP 450活性。重组细胞色素P450酶（rCYP）被用来研究参与其代谢的异构体。采用液相色谱-四极杆/飞行时间-质谱法鉴定生物转化产物。发现4种还原酶（2C 18、2C 19、2D 6和3A 4）参与mitragynine的代谢。7-羟基mitragynine（其对μ-阿片受体的亲和力是吗啡的10倍）仅由3A 4产生。9-O-去甲基mitragynine是体外最丰富的代谢物（也是kratom使用者尿液中最常见的代谢物），由2C 19、3A 4和2D 6产生。16-羧米曲宁由rCYP 2D 6、2C 19和2C 18产生。2C 19是唯一负责9-O-去甲基-16-羧基mitragynine的形成。在体外研究中进行了比较，I相代谢产物的尿液中涉及的情况下，mitragynine。
Mitragyna speciosa (Kratom) has emerged as a recreational drug and a substance of medicinal intrigue. Although the drug was initially used recreationally for its sedating and euphoric effects, more recently its use has been associated with the non-medically supervised treatment of opioid abstinence syndrome. Mitragynine is the principal pharmacologically active alkaloid in kratom. Although metabolites of mitragynine have been identified, the cytochrome P450 (CYP450) enzymes responsible for its biotransformation are still under investigation. The goal of this study was to contribute further knowledge regarding CYP450 activity as it relates to mitragynine. Recombinant cytochrome P450 enzymes (rCYPs) were used to investigate the isoforms involved in its metabolism. Biotransformational products were identified using liquid chromatography-quadrupole/time of flight-mass spectrometry. Four rCYP enzymes (2C18, 2C19, 2D6 and 3A4) were found to contribute to the metabolism of mitragynine. 7-Hydroxymitragynine (which has an affinity for the mu-opioid receptor >10-folds that of morphine) was produced exclusively by 3A4. 9-O-demethylmitragynine, the most abundant metabolite in vitro (and the most prevalent metabolite in urine among kratom users) was produced by 2C19, 3A4 and 2D6. 16-Carboxymitragynine was produced by rCYPs 2D6, 2C19 and 2C18. 2C19 was solely responsible for the formation of 9-O-demethyl-16-carboxymitragynine. In vitro rCYP studies were compared with phase I metabolites in urine from cases involving mitragynine.