Cytochrome P450-dependent toxic effects of primaquine on human erythrocytes
Cytochrome P450-dependent toxic effects of primaquine on human erythrocytes
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DOI：
10.1016/j.taap.2009.07.012
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发表时间：
2009-11-15
影响因子：
3.8
通讯作者：
Walker, Larry A.
中科院分区：
文献类型：
--
作者：
Ganesan, Shobana;Tekwani, Babu L.;Walker, Larry A.
伯氨喹是一种8-氨基喹啉，是根治复发性疟疾的首选药物。伯氨喹的使用由于其血液毒性而受到限制，特别是在葡萄糖-6-磷酸脱氢酶缺乏[G6 PD（-）]的人群中。生物转化似乎是伯氨喹抗感染和血液学毒性的核心，但其机制仍不清楚。伯氨喹的代谢研究由于潜在的血液毒性代谢物的反应性质而受到阻碍。已开发了体外代谢相关血液毒性试验。将药物与正常或G6 PD（-）红细胞、微粒体或重组细胞色素P-450（CYP）亚型共孵育，可原位产生潜在的血液毒性代谢产物，其与红细胞相互作用产生血液毒性。高铁血红蛋白的形成，实时生成的活性氧中间体（ROI）和消耗的活性硫醇监测作为多个生化终点的血液毒性。单独使用伯氨喹不会产生任何血液毒性，而在人或小鼠肝微粒体存在下，伯氨喹可显著增加高铁血红蛋白形成和ROI生成。多种CYP 2 E1、CYP 2B 6、CYP 1A 2、CYP 2D 6和CYP 3A 4亚型共同参与伯氨喹的血液毒性。这一点通过选择性β-内酰胺酶抑制剂（即塞替派（CYP 2B 6）、氟西汀（CYP 2D 6）和三乙酰竹桃霉素（CYP 3A 4））对伯氨喹血液毒性的显著抑制得到进一步证实。伯氨喹在G6 PD（-）和正常人红细胞中引起类似的高铁血红蛋白形成。然而，由于伯氨喹毒性，G6 PD（-）红细胞比正常红细胞遭受更高的氧化应激和巯基消耗。这些结果提供了关于导致血液毒性的β-羟喹异构体的重要见解，并可能有助于控制伯氨喹的毒性，以增加其治疗效用。(C)2009年由Elsevier Inc.出版
Primaquine, an 8-aminoquinoline, is the drug of choice for radical cure of relapsing malaria. Use of primaquine is limited due to its hemotoxicity, particularly in populations with glucose-6-phosphate dehydrogenase deficiency [G6PD(-)]. Biotransformation appears to be central to the anti-infective and hematological toxicities of primaquine, but the mechanisms are still not well understood. Metabolic studies with primaquine have been hampered due to the reactive nature of potential hemotoxic metabolites. An in vitro metabolism-linked hemotoxicity assay has been developed. Co-incubation of the drug with normal or G6PD(-) erythrocytes, microsomes or recombinant cytochrome P-450 (CYP) isoforms has allowed in situ generation of potential hemotoxic metabolite(s), which interact with the erythrocytes to generate hemotoxicity. Methemoglobin formation, real-time generation of reactive oxygen intermediates (ROIs) and depletion of reactive thiols were monitored as multiple biochemical end points for hemotoxicity. Primaquine alone did not produce any hemotoxicity, while a robust increase was observed in methemoglobin formation and generation of ROIs by primaquine in the presence of human or mouse liver microsomes. Multiple CYP isoforms (CYP2E1, CYP2B6, CYP1A2, CYP2D6 and CYP3A4) variably contributed to the hemotoxicity of primaquine. This was further confirmed by significant inhibition of primaquine hemotoxicity by the selective CYP inhibitors, namely thiotepa (CYP2B6), fluoxetine (CYP2D6) and troleandomycin (CYP3A4). Primaquine caused similar methemoglobin formation in G6PD(-) and normal human erythrocytes. However, G6PD(-) erythrocytes suffered higher oxidative stress and depletion of thiols than normal erythrocytes due to primaquine toxicity. The results provide significant insights regarding CYP isoforms contributing to hemotoxicity and may be useful in controlling toxicity of primaquine to increase its therapeutic utility. (C) 2009 Published by Elsevier Inc.