Potential Pro-Inflammatory Effect of Vitamin E analogs through Mitigation of Tetrahydrocannabinol (ThC) Binding to the Cannabinoid 2 Receptor.

Introduction:
This text provides an in-depth analysis of the interaction between vitamin E and the cannabinoid 2 receptor (CB2R), and its impact on tetrahydrocannabinol (ThC) binding. The study employs in vitro assays, docking, and molecular dynamics (MD) simulations to understand the role of vitamin E in modulating ThC binding to CB2R.

Key Points:

* The study used in vitro assays to show that vitamin E acetate could decrease ThC binding to CB2R and possibly decrease ThC-CBR2 mediated anti-inflammatory activity.
* MD simulations revealed that hydrophobic vitamin Es have a greater inclination to interact with the phospholipid bilayer of the membrane than with CB2R.
* The number of hydrogen bonds between vitamin E and the phospholipid was found to be greater than the hydrogen bonds formed between vitamin E and CB2R.
* The position of vitamin Es was investigated along the depth of the phospholipid bilayer membrane, and it was found that if vitamin Es can access and interact with the lower POPC layer, they can travel from the upper leaflet to the lower leaflet of the cell membrane.
* The contact frequency was monitored between CB2R amino acid residues and vitamin Es throughout the MD simulations. The results showed that vitamin Es interact with different helices of CB2R, which may affect the ThC binding with CB2R.
* The study found that in the presence of vitamin E, water molecules were attracted to the ligand binding cavity, leading to a new opening and a new interaction pattern, reducing ThC binding to CB2R.

Main Message:
The study highlights the potential role of vitamin E in limiting the effect of ThCs and its implications on the reported pathology of EVaLI. The findings suggest that vitamin E acetate, used as a diluent of ThC in e-cigarettes, could decrease ThC binding to CB2R, leading to downregulation of the anti-inflammatory and anti-oxidative responses of ThCs, which may contribute to lung inflammation with chronic exposure. Therefore, more research is needed to further understand the role of vitamin E/acetate in EVaLI outbreaks.

Manandhar a, haron Mh, Ross Sa, Klein ML, Elokely KM. Potential Pro-Inflammatory Effect of Vitamin E analogs through Mitigation of Tetrahydrocannabinol (ThC) Binding to the Cannabinoid 2 Receptor. International journal of molecular sciences. 2022;23(8). doi:10.3390/ijms23084291