Metabolism of JQ1, an inhibitor of bromodomain and extra terminal bromodomain proteins, in human and mouse liver microsomes
Metabolism of JQ1, an inhibitor of bromodomain and extra terminal bromodomain proteins, in human and mouse liver microsomes
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DOI：
10.1093/biolre/ioaa043
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发表时间：
2020-08-01
影响因子：
3.6
通讯作者：
Matzuk, Martin M.
中科院分区：
文献类型：
--
作者：
Li, Feng;MacKenzie, Kevin R.;Matzuk, Martin M.
JQ 1是布罗莫结构域和额外末端（BET）蛋白家族的小分子抑制剂，其有效地抑制布罗莫结构域睾丸特异性蛋白（BRDT），其对于精子发生是必需的。JQ 1治疗通过靶向小鼠雄性生殖细胞中BRDT的活性产生可逆的避孕作用，验证BRDT作为雄性避孕靶点。虽然JQ 1具有良好的物理特性，但它的半衰期很短。由于外源性物质代谢的细节在候选药物的优化和确定代谢在药物功效中的作用方面起着重要作用，因此我们研究了JQ 1在人和小鼠肝微粒体中的代谢。我们提出了第一个全面的JQ 1代谢在肝微粒体中，区分九个JQ 1代谢物，包括三个单羟基化，一个脱叔丁基化，两个二羟基化，一个单羟基化/脱氢，一个单羟基化脱叔丁基化和一个二羟基化/脱氢的JQ 1变体。人和小鼠肝微粒体中的主要代谢产物（M1）在融合三环核心上单羟基化。使用重组细胞色素P450（CYP）酶，化学抑制剂和肝S9部分的Cyp 3a-null小鼠，我们确定的酶，有助于这些代谢产物的形成。细胞色素P450家族3亚家族A成员4（CYP 3A 4）是体外JQ 1代谢物产生的主要贡献者，CYP 3A 4/5抑制剂酮康唑强烈抑制人和小鼠肝微粒体中的JQ 1代谢。我们的研究结果表明，JQ 1的半衰期和疗效可能会改善在体内通过共同管理的选择性BRDT抑制剂，从而影响使用JQ 1作为探针的BRDT活性在精子发生和探针或治疗在其他系统。
JQ1 is a small-molecule inhibitor of the bromodomain and extra terminal (BET) protein family that potently inhibits the bromodomain testis-specific protein (BRDT), which is essential for spermatogenesis. JQ1 treatment produces a reversible contraceptive effect by targeting the activity of BRDT in mouse male germ cells, validating BRDT as a male contraceptive target. Although JQ1 possesses favourable physical properties, it exhibits a short half-life. Because the details of xenobiotic metabolism play important roles in the optimization of drug candidates and in determining the role of metabolism in drug efficacy, we investigated the metabolism of JQ1 in human and mouse liver microsomes. We present the first comprehensive view of JQ1 metabolism in liver microsomes, distinguishing nine JQ1 metabolites, including three monohydroxylated, one de-tert-butylated, two dihydroxylated, one monohydroxylated/dehydrogenated, one monohydroxylated-de-tert-butylated and one dihydroxylated/dehydrogenated variant of JQ1. The dominant metabolite (M1) in both human and mouse liver microsomes is monohydroxylated on the fused three-ring core. Using recombinant cytochrome P450 (CYP) enzymes, chemical inhibitors and the liver S9 fraction of Cyp3a-null mice, we identify enzymes that contribute to the formation of these metabolites. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is the main contributor to the production of JQ1 metabolites in vitro, and the CYP3A4/5 inhibitor ketoconazole strongly inhibits JQ1 metabolism in both human and mouse liver microsomes. Our findings suggest that JQ1 half-life and efficacy might be improved in vivo by co-administration of a selective CYP inhibitor, thereby impacting the use of JQ1 as a probe for BRDT activity in spermatogenesis and as a probe or therapeutic in other systems.