SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues

Abstract

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.

High and Low Levels of ABCB1 Expression Are Associated with Two Distinct Gene Signatures in Lung Tissue of Pulmonary TB Patients with High Inflammation Activity

“…On the samples obtained in 2017-2018, we investigated the expression of the most clinically relevant ABC drug transporter genes, such as ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP), expressed in the lungs [50]. Our findings revealed higher expression of the ABCB1 gene in patients with active inflammation activity.…”

Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections

“…However, the data presented herein demonstrated that the potency and toxicities of some drugs, especially NA inhibitors were cell-system dependent. This was not unexpected since different cell types may have unequal distributions of drug metabolizing enzymes and membrane transporters [ 201 ], and certain antiviral agents (e.g., remdesivir and nirmatrelvir) are substrates of the Cytochrome P450 enzymes, P-glycoprotein, and other cell membrane transporters [ 202 , 203 ]. Also, NA phosphorylation may be cell-dependent [ 138 , 139 ].…”