CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor.
CYP1A1 and 1B1-mediated metabolic pathways of dolutegravir, an HIV integrase inhibitor.
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DOI：
10.1016/j.bcp.2018.10.012
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发表时间：
2018-12
影响因子：
5.8
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Zhu J;Wang P;Li F;Lu J;Shehu AI;Xie W;McMahon D;Ma X
Dolutegravir（DTG）是一种有效的整合酶抑制剂，是治疗人类免疫缺陷病毒（HIV）的推荐初始方案的一部分。先前的报告表明，DTG的清除率在当前吸烟者中高于非吸烟者，但其机制尚不清楚。使用代谢组学方法，M4（醛）被鉴定为DTG的新代谢产物。此外，发现M4的形成是由细胞色素P450（P450）1A 1和1B 1介导的，这两种酶可以被吸烟高度诱导。CYP 1A 1和1B 1也被确定为促进M1（DTG的N-脱烷基代谢产物）和M5（醛）形成的主要酶。此外，用2，3，7，8-四氯二苯并-对-二恶英（CYP 1A 1和1B 1的诱导剂）处理的小鼠肺中M1和M4的产生显著增加。总之，本研究揭示了CYP 1A 1和1B 1介导的DTG代谢途径。这些数据表明，接受DTG的HIV感染者应谨慎吸烟，药物或暴露于诱导CYP 1A 1和1B 1的环境化学物质。
Dolutegravir (DTG), a potent integrase inhibitor, is part of a recommended initial regimen for the treatment of human immunodeficiency virus (HIV). Prior reports demonstrated that the clearance of DTG was higher in current smokers than nonsmokers, but the mechanism remains unclear. Using a metabolomic approach, M4 (an aldehyde) was identified as a novel metabolite of DTG. In addition, the formation of M4 was found to be mediated by cytochrome P450 (CYP) 1A1 and 1B1, the enzymes that can be highly induced by cigarette smoking. CYP1A1 and 1B1 were also identified as the major enzymes contributing to the formation of M1 (an N- dealkylated metabolite of DTG) and M5 (an aldehyde). Furthermore, the production of M1 and M4 was significantly increased in the lung of mice treated with 2,3,7,8- tetrachlorodibenzo-p-dioxin, an inducer of CYP1A1 and 1B1. In summary, the current study uncovered the CYP1A1 and 1B1-mediated metabolic pathways of DTG. These data suggest that persons with HIV infection receiving DTG should be cautious to cigarettes, and drugs, or exposure to environmental chemicals that induce CYP1A1 and 1B1.
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影响因子：
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