THC Inhibits Important Human Enzyme, Study Finds
THC can inhibit the activity of an important enzyme called autotaxin, according to new research.
The study, published in Life Science Alliance, used biological assays to demonstrate that THC, as well as its derivative 9(R)-Δ6a,10a-THC (6a10aTHC) and its acidic precursor tetrahydrocannabinolic acid (THCA), can inhibit the catalytic activity of autotaxin.
During their investigations, the European Molecular Biology Laboratory (EMBL) research team were also able to use crystallographic data to determine the three-dimensional structure of THC bound with autotaxin.
Autotaxin plays an important role in mediating many important functions in the body and has been linked to conditions such as cancer and inflammation. In light of their findings, which lay the molecular basis for explaining how THC interacts with autotaxin, the researchers suggest that THC may soon become an attractive candidate for drug development in these areas.
What is autotaxin?
Autotaxin (ATX) is an enzyme that is primarily responsible for producing lysophosphatidic acid (LPA) in the blood. This ATX-LPA signaling axis has been linked to numerous physiological and pathological processes, including vascular and neuronal development, neuropathic pain, and other immune-mediated diseases such as cancer and multiple sclerosis.
“Autotaxin is an essential enzyme in human beings,” first author and PhD student Mathias Eymery, said in a statement. “It is responsible for the production of LPA, a major membrane-derived lipid signaling molecule that mediates many different cellular functions. Dysregulations of LPA production by autotaxin are known to have a role in the development of cancer, inflammation, or pulmonary fibrosis.”
The endocannabinoid system is another important signaling system in the human body, and has receptors spread throughout the central and peripheral nervous systems. As the researchers explain in their paper, the wider endocannabinoid system does overlap with other signaling pathways including LPA and its receptors.
Notably, the body’s endocannabinoid system can be manipulated by using cannabis, which introduces exogenous cannabinoids such as THC and CBD into the body. Given this overlap of the endocannabinoid system and the LPA signaling pathway, the researchers set out to test whether cannabinoid compounds might also affect LPA signaling.
THC can bind to ATX and inhibit its function
Using biochemical assay validation, the EMBL researchers evaluated the activity of two ATX isoforms (ATX-β and ATX-γ) against a diverse range of cannabinoids, including: THC, THCA, 6a10aTHC, and CBD, as well as the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the synthetic cannabinoid JWH018.
They found that THC and its derivative both potently inhibited the catalysis of each ATX isoform in the assay. THCA also showed some amount of inhibition, but this was less pronounced than the other two compounds. Interestingly, the synthetic cannabinoid and the two endocannabinoids had no significant effects on the catalytic activity of ATX, while CBD only very weakly affected one of the isoforms.
The researchers also sought to investigate the binding interface of ATX to THC. Using crystallographic data, a 3D molecular model of the binding interface was able to be constructed, confirming that both THC molecules and 6a10aTHC molecules have a very good fit against ATX’s active site.
ATX inhibitors could help combat glaucoma and fibrosis
The researchers are careful to point out that while their findings do point to a potent inhibition of ATX catalysis by THC and similar cannabinoids in vitro, more research is still needed to confirm whether this holds true in vivo when cannabis products are consumed.
However, they do note that LPA is already known to be present in human saliva and ATX expression has also been detected in salivary gland tissue. Since cannabis is largely consumed via smoking, the researchers postulate that the cannabis smoke would certainly come into contact with saliva and therefore would potentially have the opportunity to affect ATX-LPA signaling in vivo.
Studying whether THC can inhibit ATX in vivo is relevant, they explain, as ATX inhibitors are already the subject of clinical trials and advanced research efforts. Studying this relationship could also help scientists to better understand the mechanisms behind medicinal cannabis’ effects.
For example, it was recently discovered that patients with glaucoma tend to have elevated levels of ATX and LPA, and that intraocular pressure (IOP) (the main cause of glaucoma) can be reduced in animals given an ATX inhibitor. Separately, cannabis researchers have observed that THC appears to reduce IOP in healthy individuals, but the mechanism behind this was unclear.
“Our data may explain the molecular basis for the therapeutic effect of medical cannabis in glaucoma patients, as THC could feasibly reduce the formation of LPA by inhibiting the enzymatic activity of ATX,” the researchers wrote.
Additionally, several ATX inhibitors are currently being investigated as potential therapeutics for idiopathic pulmonary fibrosis. However, a major phase three clinical trial of an advanced ATX inhibitor was recently discontinued as the “benefit-risk profile no longer supports continuing the study.” In contrast, there is an FDA-approved formulation of THC (dronabinol) that is accepted to have a tolerable side effect profile.
“In this context, our observation that THC is a partial inhibitor of ATX is of great interest, because this molecule [THC] is an FDA-approved drug, which could reduce LPA levels incompletely,” the researchers added.
