How cigarette smoke is motivating COVID-19 drug research

The findings appear in the journal scientific report. While smoking is associated with health risks and increased severity of COVID-19, some reports have suggested fewer COVID cases among smokers.

“We must emphasize the existence of strong evidence that smoking increases the severity of COVID-19. But the mechanism we discovered here deserves further investigation as a potential tool to fight SARS-CoV-2 infection,” said Keiji Tanimoto of Hiroshima University’s Research Institute for Radiation Biology and Medicine, who is one of the authors of the paper.

Cigarette smoke contains polycyclic aromatic hydrocarbons (PAHs) that can bind to and activate aryl hydrocarbon receptors (AHRs). A receptor is a structure on or inside a cell surface that is shaped to receive and bind to a particular substance. AHRs are receptors inside mammalian cells that can induce a wide range of cellular activities through their ability to increase or decrease the expression of certain genes.

The researchers examined the effect of chemicals that activate AHR on genes that control the production of ACE2, a receptor protein on the surface of certain cells that the SARS-CoV-2 virus can hook into. The virus that causes COVID-19 binds to the ACE2 protein to enter and infect human cells.

The scientists found that cells in the oral cavity, lung, and liver had the highest ACE2 expression. These cells were then subjected to various doses of cigarette smoke extracts for 24 h.

The scientists found that the greater the amount of cigarette-smoke extract on the cells, the greater the effect on CYP1A1 gene expression in liver and lung cells. The over-activity of the gene results in less production of the ACE2 protein that the virus uses to enter cells. However, this effect was not as pronounced in cells of the oral cavity.

To understand why this was happening, the researchers used RNA sequencing analysis to examine gene expression. They found that the smoke extract increased the expressions of genes related to key processes within the cell that regulate AHR.

The researchers then studied the effects of two drugs that can activate AHR in liver cells. The first drug is a derivative of the amino acid tryptophan, and the second is omeprazole, a drug widely used to treat acid reflux and peptic ulcers.

RNA sequencing data suggested that the CYP1A1 gene strongly induced AHR activators in liver cells, and strongly inhibited the production of ACE2 protein.

The researchers concluded that the two drugs, which act as activators of AHR, may suppress the production of ACE2 in mammalian cells and, thus, reduce the ability of the SARS-CoV-2 virus to infect cells. Huh.

Scientists are now testing two drugs in pre-clinical and clinical trials for the treatment of Kovid-19.