Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin
Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin
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DOI：
10.1046/j.1365-2125.1999.00044.x
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发表时间：
1999-10-01
影响因子：
3.4
通讯作者：
Ashton, M
中科院分区：
文献类型：
--
作者：
Svensson, USH;Ashton, M
目的本研究旨在确定参与青蒿素代谢的特异性人细胞色素P450（CYP 450）酶。研究了对CYP 450各亚型选择性化学抑制剂对青蒿素在人肝微粒体中代谢的影响。采用基于树的回归模型评价了个体CYP 450同工酶对人肝微粒体中青蒿素代谢的相对贡献：结果重组CYP 2B 6对青蒿素的代谢证实了CYP 2B 6参与青蒿素的代谢，奥芬那君（76%）对人肝微粒体中青蒿素消失的抑制作用以及基于树的回归模型中对CYP 2B 6的主要纳入。重组CYP 3A 4对青蒿素的代谢具有催化活性，但其代谢率仅为重组CYP 2B 6的10%。基于树的回归模型表明CYP 3A 4在CYP 2B 6低表达的个体中具有重要性。尽管酮康唑对人肝微粒体中青蒿素代谢的抑制率为46%，但与单独使用奥芬那君相比，与酮康唑和奥芬那君一起孵育对青蒿素代谢的抑制并未增加。醋竹桃霉素不能抑制青蒿素的代谢。青蒿素在重组CYP 2A 6中的代谢率为重组CYP 2B 6的15%。8-methoxypropylene（CYP 2A 6抑制剂）的抑制青蒿素在人肝微粒体中的代谢是82%，但CYP 2A 6活性不包括在回归tree.Conclusions青蒿素在人肝微粒体中的代谢主要是介导的CYP 2B 6与CYP 3A 4可能的次要贡献，在个人与CYP 2B 6低表达。CYP 2A 6对青蒿素代谢的贡献可能不太重要。
Aims The study aimed to identify the specific human cytochrome P450 (CYP450) enzymes involved in the metabolism of artermisinin.Methods Microsomes from human B-lymphoblastoid cell lines transformed with individual CYP450 cDNAs were investigated for their capacity to metabolize artemisinin. The effect on artemisinin metabolism in human liver microsomes by chemical inhibitors selective for individual forms of CYP450 was investigated. The relative contribution of individual CYP450 isoenzymes to artemisinin metabolism in human liver microsomes was evaluated with a tree-based regression model of: artemisinin disappearance rate and specific CYP450 activities.Results The involvement of CYP2B6 in artermisinin metabolism was demonstrated by metabolism of artemisinin by recombinant CYP2B6, inhibition of artemisinin disappearance in human liver microsomes by orphenadrine (76%) and primary inclusion of CYP2B6 in the tree-based regression model. Recombinant CYP3A4 was catalytically competent in metabolizing artemisinin, although the rate was 10% of that for recombinant CYP2B6. The tree-based regression model suggested CYP3A4 to be of importance in individuals with low CYP2B6 expression. Even though ketoconazole inhibited artemisinin metabolism in human liver microsomes by 46%, incubation with ketoconazole together with orphenadrine did not increase the inhibition of artemisinin metabolism compared to orphenadrine alone. Troleandomycin failed to inhibit artemisinin metabolism. The rate of artemisinin metabolism in recombinant CYP2A6 was 15% of that for recombinant CYP2B6. The inhibition of artemisinin metabolism in human liver microsomes by 8-methoxypsoralen (a CYP2A6 inhibitor)was 82% but CYP2A6 activity was not included in the regression tree.Conclusions Artemisinin metabolism in human liver microsomes is mediated primarily by CYP2B6 with probable secondary contribution of CYP3A4 in individuals with low CYP2B6 expression. The contribution of CYP2A6 to artemisinin metabolism is likely of minor importance.