Nwabufo Chukwunonso K, Hoque Md Tozammel, Yip Lily, Khara Maliha, Mubareka Samira, Pollanen Michael S, Bendayan Reina
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
OneDrug, Toronto, ON, Canada.
Front Pharmacol. 2023 Apr 27;14:1124693. doi: 10.3389/fphar.2023.1124693. eCollection 2023.
SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit the clinical efficacy and safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Also, we assessed the role of 2 inflammatory and 4 regulatory proteins in modulating the dysregulation of DMETs in human lung tissues. We showed for the first time that SARS-CoV-2 infection dysregulates CYP3A4 and UGT1A1 at the mRNA level, as well as P-gp and MRP1 at the protein level, in Vero E6 cells and postmortem human lung tissues, respectively. We observed that at the cellular level, DMETs could potentially be dysregulated by SARS-CoV-2-associated inflammatory response and lung injury. We uncovered the pulmonary cellular localization of CYP1A2, CYP2C8, CYP2C9, and CYP2D6, as well as ENT1 and ENT2 in human lung tissues, and observed that the presence of inflammatory cells is the major driving force for the discrepancy in the localization of DMETs between COVID-19 and control human lung tissues. Because alveolar epithelial cells and lymphocytes are both sites of SARS-CoV-2 infection and localization of DMETs, we recommend further investigation of the pulmonary pharmacokinetic profile of current COVID-19 drug dosing regimen to improve clinical outcomes.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）与不同组织（尤其是肺部，主要受累器官）中的药物代谢酶和膜转运蛋白（DMETs）之间的相互作用，可能会限制有前景的新型冠状病毒肺炎（COVID-19）药物的临床疗效和安全性。在此，我们研究了SARS-CoV-2感染是否会导致Vero E6细胞以及COVID-19患者的尸检肺组织中25种临床相关DMETs的表达失调。此外，我们评估了2种炎症蛋白和4种调节蛋白在调节人肺组织中DMETs失调方面的作用。我们首次表明，SARS-CoV-2感染分别在Vero E6细胞和尸检人肺组织中，在mRNA水平上使细胞色素P450 3A4（CYP3A4）和尿苷二磷酸葡萄糖醛酸基转移酶1家族A成员1（UGT1A1）失调，在蛋白水平上使P-糖蛋白（P-gp）和多药耐药相关蛋白1（MRP1）失调。我们观察到，在细胞水平上，DMETs可能会因SARS-CoV-2相关的炎症反应和肺损伤而失调。我们揭示了细胞色素P450 1A2（CYP1A2）、细胞色素P450 2C8（CYP2C8）、细胞色素P450 2C9（CYP2C9）和细胞色素P450 2D6（CYP2D6）以及人肺组织中ENT1和ENT2的肺细胞定位，并观察到炎症细胞的存在是COVID-19患者与对照人肺组织之间DMETs定位差异的主要驱动力。由于肺泡上皮细胞和淋巴细胞都是SARS-CoV-2感染和DMETs定位的部位，我们建议进一步研究当前COVID-19药物给药方案的肺药代动力学特征，以改善临床结局。
