Effects of MAO-A and CYP450 on primaquine metabolism in healthy volunteers
Effects of MAO-A and CYP450 on primaquine metabolism in healthy volunteers
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DOI：
10.1007/s00436-019-06210-3
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发表时间：
2019-03-01
影响因子：
2
通讯作者：
Makmor-Bakry, Mohd
中科院分区：
文献类型：
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作者：
Ariffin, Norliza Mat;Islahudin, Farida;Makmor-Bakry, Mohd
消除间日疟原虫疟疾寄生虫感染仍然具有挑战性。主要问题之一是其形成休眠子的能力，这可能导致反复感染。目前，伯氨喹是唯一用于治疗休眠子的药物。然而，伯氨喹的作用可能因人而异。这项工作的目的是确定通过伯氨喹代谢和宿主遗传学减少间日疟原虫复发的新措施。对健康志愿者 (n=53) 进行了 MAO-A、CYP2D6、CYP1A2 和 CYP2C19 及其在伯氨喹代谢中的作用的基因研究。获得消除速率常数（K-e）和代谢物与母体药物浓度比（Cm/Cp）来评估伯氨喹代谢。等位基因和基因型分析表明，MAO-A（rs6323，891G>T）、CYP2D6（rs1065852，100C>T）和CYP2C19（rs4244285，19154G>A）多态性显着影响伯氨喹代谢。 CYP1A2 (rs762551, -163C>A) 不影响伯氨喹代谢。在单倍型分析中，多态性 GG-MAO-A (891G>T)、CT-CYP2D6 (100C>T) 和 GG-CYP2C19 (19154G>A) 个体与多态性 TT-MAO-A 个体之间 K-e (p=0.00) 和 Cm/Cp (p=0.05) 存在显着差异。 (891G>T)、TT-CYP2D6 (100C>T) 和 AA-CYP2C19 (19154G>A)，以及多态性 GG-MAO-A (891G>T)、TT-CYP2D6 (100C>T) 和 GA-CYP2C19 (19154G>A)。因此，具有 CYP2D6 多态性的个体具有较慢的伯氨喹代谢活性。伯氨喹代谢中遗传作用的潜在意义及其探索可能有助于进一步优化间日疟原虫感染的管理。
Eliminating the Plasmodium vivax malaria parasite infection remains challenging. One of the main problems is its capacity to form hypnozoites that potentially lead to recurrent infections. At present, primaquine is the only drug used for the management of hypnozoites. However, the effects of primaquine may differ from one individual to another. The aim of this work is to determine new measures to reduce P. vivax recurrence, through primaquine metabolism and host genetics. A genetic study of MAO-A, CYP2D6, CYP1A2 and CYP2C19 and their roles in primaquine metabolism was undertaken of healthy volunteers (n=53). The elimination rate constant (K-e) and the metabolite-to-parent drug concentration ratio (Cm/Cp) were obtained to assess primaquine metabolism. Allelic and genotypic analysis showed that polymorphisms MAO-A (rs6323, 891G>T), CYP2D6 (rs1065852, 100C>T) and CYP2C19 (rs4244285, 19154G>A) significantly influenced primaquine metabolism. CYP1A2 (rs762551, -163C>A) did not influence primaquine metabolism. In haplotypic analysis, significant differences in K-e (p=0.00) and Cm/Cp (p=0.05) were observed between individuals with polymorphisms, GG-MAO-A (891G>T), CT-CYP2D6 (100C>T) and GG-CYP2C19 (19154G>A), and individuals with polymorphisms, TT-MAO-A (891G>T), TT-CYP2D6 (100C>T) and AA-CYP2C19 (19154G>A), as well as polymorphisms, GG-MAO-A (891G>T), TT-CYP2D6 (100C>T) and GA-CYP2C19 (19154G>A). Thus, individuals with CYP2D6 polymorphisms had slower primaquine metabolism activity. The potential significance of genetic roles in primaquine metabolism and exploration of these might help to further optimise the management of P. vivax infection.