Adverse effects of anti ‐ Covid ‐ 19 drug candidates and alcohol on hepatocyte cellular stress responses – Khalatbari – – Hepatology Communications


During the pandemic, dexamethasone, remdesivir, hydrochloquine, thapsigargine, camostat mesylate, and pralatrexate were reused drugs for COVID-19. However, the side effects on the liver associated with anti-COVID therapies are unknown. Cellular stresses by these drugs at 0-30 M were investigated using HepG2, Huh7 and / or primary human hepatocytes. Dexamethasone or remdesivir induced endoplasmic reticulum stress with increased Xbp1 and an autophagic response with increased accumulation of LC3-II. Dexamethasone and remdesivir had additive effects on stress responses in liver cells, further increasing ATF4 and CHOP expression and cell death. Pretreatment with alcohol (50 mM) and dexamethasone induced greater cellular stress responses than dexamethasone and remdesivir. Pralatrexate induced Golgi fragmentation, G0 / G1 phase cell cycle arrest, PARP and caspase activations, and cell death. Pralatrexate and alcohol had synergistic effects on the cell death mediators of Bim, caspase3 and PARP. Camostat mesylate protease inhibitor and thapsigargine induced an autophagic response and mitochondrial stress with altered mitochondrial membrane potential, Bcl2 and cytochrome C. Thapsigargine and hydrochloquine induced markers of autophagic response of ULK, LC3-II, Beclin1 and Atg5 and a severe ER stress marker CHOP. These results suggest that anti-COVID-19 drugs, especially with drug-drug or alcohol-drug combinations, induce cellular stress responses and damage in liver cells.


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