Sakamuru Srilatha, Travers Jameson, Klumpp-Thomas Carleen, Huang Ruili, Witt Kristine L, Ferguson Stephen S, Simmons Steven O, Reif David M, Simeonov Anton, Xia Menghang
Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
Division of Translational Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC 27709, USA.
Int J Mol Sci. 2025 May 22;26(11):4976. doi: 10.3390/ijms26114976.
Cytochrome P450 (CYP) enzymes are membrane-bound hemoproteins crucial for drug and xenobiotic metabolism. While more than 50 CYPs have been identified in humans, the isoforms from CYP1, 2, and 3 families contribute to the metabolism of about 80% of clinically approved drugs. To evaluate the effects of environmental chemicals on the activities of these important CYP enzyme families, we screened the Tox21 10K compound library to identify chemicals that inhibit CYP1A2, 2C9, 2C19, 2D6, and 3A4 enzymes. The data obtained from these five screenings were analyzed to reveal the structural classes responsible for inhibiting multiple and/or selective CYPs. Some known structural compound classes exhibiting pan-CYP inhibition, such as azole fungicides, along with established clinical inhibitors of CYPs, including erythromycin and verapamil inhibiting CYP3A4 and paroxetine and terbinafine inhibiting CYP2D6, were all confirmed in the current study. In addition, some selective CYP inhibitors, previously unknown but with potent activity (IC values < 1 µM), were identified. Examples included yohimbine, an indole alkaloid, and loteprednol, a corticosteroid, which showed inhibitory activity in CYP2D6 and 3A4 assays, respectively. These findings suggest that assessment of a candidate compound's impact on CYP function may allow pre-emptive mitigation of potential adverse reactions and toxicity during drug development or toxicological characterization of environmental chemicals.
细胞色素P450（CYP）酶是膜结合血红蛋白，对药物和外源性物质的代谢至关重要。虽然在人类中已鉴定出50多种CYP，但CYP1、2和3家族的同工型参与了约80%临床批准药物的代谢。为了评估环境化学物质对这些重要CYP酶家族活性的影响，我们筛选了Tox21 10K化合物库，以鉴定抑制CYP1A2、2C9、2C19、2D6和3A4酶的化学物质。对这五项筛选获得的数据进行分析，以揭示负责抑制多种和/或选择性CYP的结构类别。在本研究中证实了一些已知的具有泛CYP抑制作用的结构化合物类别，如唑类杀菌剂，以及已确定的CYP临床抑制剂，包括抑制CYP3A4的红霉素和维拉帕米，以及抑制CYP2D6的帕罗西汀和特比萘芬。此外，还鉴定了一些以前未知但具有强效活性（IC值<1µM）的选择性CYP抑制剂。例子包括吲哚生物碱育亨宾和皮质类固醇氯替泼诺，它们分别在CYP2D6和3A4测定中显示出抑制活性。这些发现表明，评估候选化合物对CYP功能的影响可能有助于在药物开发或环境化学物质的毒理学特征研究期间预先减轻潜在的不良反应和毒性。
