Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Drug Metab Pers Ther. 2021 Apr 7;36(3):205-214. doi: 10.1515/dmpt-2020-0160.
The function and expression of cytochrome P450 (CYP) drug metabolizing enzymes is highly variable, greatly affecting drug exposure, and therapeutic outcomes. The expression of these enzymes is known to be controlled by many transcription factors (TFs), including ligand-free estrogen receptor alpha (ESR1, in the absence of estrogen). However, the relationship between the expression of ESR1, other TFs, and CYP enzymes in human liver is still unclear.
Using real-time PCR, we quantified the mRNA levels of 12 CYP enzymes and nine TFs in 246 human liver samples from European American (EA, n = 133) and African American (AA, n = 113) donors.
Our results showed higher expression levels of ESR1 and six CYP enzymes in EA than in AA. Partial least square regression analysis showed that ESR1 is the top-ranking TF associating with the expression of eight CYP enzymes, six of which showed racial difference in expression. Conversely, four CYP enzymes without racial difference in expression did not have ESR1 as a top-ranking TF. These results indicate that ESR1 may contribute to variation in CYP enzyme expression between these two ancestral backgrounds.
These results are consistent with our previous study showing ESR1 as a master regulator for the expression of several CYP enzymes. Therefore, factors affecting ESR1 expression may have broad influence on drug metabolism through altered expression of CYP enzymes.
细胞色素 P450（CYP）药物代谢酶的功能和表达具有高度可变性，极大地影响药物暴露和治疗效果。这些酶的表达已知受许多转录因子（TFs）的控制，包括无配体的雌激素受体 alpha（ESR1，在没有雌激素的情况下）。然而，人类肝脏中 ESR1、其他 TF 和 CYP 酶的表达之间的关系尚不清楚。
我们使用实时 PCR 定量分析了来自欧洲裔美国人（EA，n = 133）和非裔美国人（AA，n = 113）供体的 246 个人肝样本中 12 种 CYP 酶和 9 种 TF 的 mRNA 水平。
我们的结果表明，EA 中 ESR1 和六种 CYP 酶的表达水平高于 AA。偏最小二乘回归分析表明，ESR1 是与八种 CYP 酶表达相关的排名最高的 TF，其中六种 CYP 酶在表达上存在种族差异。相反，四种在表达上没有种族差异的 CYP 酶没有 ESR1 作为排名最高的 TF。这些结果表明，ESR1 可能导致这两个祖先后裔背景中 CYP 酶表达的差异。
这些结果与我们之前的研究一致，表明 ESR1 是几种 CYP 酶表达的主要调节因子。因此，影响 ESR1 表达的因素可能通过改变 CYP 酶的表达对药物代谢产生广泛影响。
