PRE-EXPOSURE TO ALCOHOL IMPAIRS ANTI-COVID DRUGS TREATMENTASSOCIATED CELLULAR STRESS RESPONSES IN LIVER CELLS
Alcoholism: Clinical and Experimental Research
; 46:142A, 2022.
Article
in English
| EMBASE | ID: covidwho-1937893
ABSTRACT
As the delta and omicron SARS-CoV-2 variants spread across the world, more tools to fight off serious infection have been developed. COVID antiviral drugs that can be taken orally at home could cut serious illness and reduce the risk of hospitalization and death. However, significant population of people consume alcohol before the infection and use of the antiviral drugs, which could potentiate side effects of the drugs on the liver. We investigated the role of alcohol in anti-Covid drug-induced stress responses in live cells. METHODS:
HepG2 cells or primary mouse hepatocytes (PMH) were pre-treated with alcohol (50 mMlow dose or 100 mMhigh dose) for 6-24 hours and then treated with the newly developed oral anti-Covid drugs nirmatrelvir, ritonavir, molnupiravir, and remdesivir at 10- 30 lg/ml for 6-24 hours. Unfolded protein response (UPR)/ER stress molecular markers (e.g. IRE1 GRP78, PERK, Xbp1 and CHOP), Golgi stress response (GSR) markers of GCP60, HSP47 and TFE3, and STAT3 were measured after the treatments. Cell death was assessed through double staining the liver cells with Syntox Green and Hoesche's Blue.RESULTS:
ER stress response as indicated by IRE1, Xbp1 and CHOP was insignificant or mild in either HepG2 or PMH treated individually with alcohol at the low dose, nirmatrelvir, ritonavir, molnupiravir, or remdesivir. Alcohol or remdesivir induced moderate GSR based on mRNA increase of GCP60, HSP47 and TFE3, which was accompanied with apparent Golgi fragmentation in either HepG2 or PMH. Cell death rates in HepG2 treated with alcohol, nirmatrelvir, ritonavir, molnupiravir, or remdesivir individually were less than 5%. Pre-exposure to alcohol combined with subsequent treatment with nirmatrelvir, ritonavir molnupiravir, or remdesivir significantly increased both ER stress and GSR markers and expression of phosphorylated STAT3 (p-STAT3). Most significantly, cell death rates in HepG2 or PMH were increased by 2- to 5-fold by pre-alcohol exposure plus ritonavir, nirmatrelvir, molnupiravir, or remdesivir. The organelle stress markers, p-STAT3 and cell death were all further increased in alcoholand anti-Covid drug-treated HepG2 or primary mouse hepatocytes that were pre-infected with the lentiviruses that were pseudotyped with the SARS-CoV-2 spike protein.CONCLUSION:
Our results indicate that pre-exposure to alcohol potentiates the liver cells to anti-Covid-19 drugs induced stress responses and cell death.
alcohol; endogenous compound; endoplasmic reticulum chaperone BiP; heat shock protein 47; messenger RNA; molecular marker; molnupiravir; nirmatrelvir plus ritonavir; remdesivir; STAT3 protein; virus spike protein; animal cell; animal experiment; cell death; cell organelle; cellular stress response; conference abstract; controlled study; coronavirus disease 2019; drug therapy; endoplasmic reticulum stress; gene expression; Golgi complex; Hep-G2 cell line; human; Lentivirus; liver cell; low drug dose; male; mortality rate; mouse; nonhuman; protein expression; protein phosphorylation; Severe acute respiratory syndrome coronavirus 2; transcription initiation; unfolded protein response
Full text:
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Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Alcoholism: Clinical and Experimental Research
Year:
2022
Document Type:
Article
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