A recent study has found that THC, a compound found in cannabis, has the ability to regulate the activity of an enzyme called autotaxin.
The research, published in the journal Life Science Alliance, used a variety of techniques to demonstrate that not only THC, but also a derivative of THC called 9(R)-Δ6a,10a-THC (6a10aTHC) and its acidic precursor tetrahydrocannabinolic acid (THCA), can all regulate the catalytic activity of autotaxin. The team of researchers from the European Molecular Biology Laboratory (EMBL) were also able to use crystallographic data to determine the three-dimensional structure of THC bound with autotaxin.
Autotaxin is an enzyme that plays a crucial role in mediating many important functions in the body and has been linked to various conditions such as cancer and inflammation. The findings from the study provide a molecular understanding of how THC interacts with autotaxin, and it is suggested that THC may soon become a viable candidate for drug development in these areas. The research team noted that since THC has been found to regulate autotaxin, it may have the potential to be used as a therapeutic agent in treating conditions such as cancer and inflammation, which are related to the enzyme.
What is autotaxin?
Autotaxin (ATX) is an enzyme that plays a crucial role in the human body. It is primarily responsible for producing lysophosphatidic acid (LPA) in the blood. LPA is a major membrane-derived lipid signaling molecule that mediates many different cellular functions. The ATX-LPA signaling axis has been linked to a variety of physiological and pathological processes, including vascular and neuronal development, neuropathic pain, and other immune-mediated diseases such as cancer and multiple sclerosis. Dysregulation of LPA production by autotaxin is known to have a role in the development of conditions such as cancer, inflammation, and 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. The endocannabinoid system plays an important role in regulating various physiological processes such as appetite, pain, mood, and memory. 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. 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 regulate the catalytic activity of autotaxin. They were also able to use crystallographic data to determine the three-dimensional structure of THC bound with autotaxin.
THC can bind to ATX and inhibit its function
The research team from the European Molecular Biology Laboratory (EMBL) conducted a series of experiments to determine the effects of various cannabinoids on the activity of ATX. They used a method called biochemical assay validation to test the activity of two different forms of the enzyme (ATX-β and ATX-γ) against a diverse range of cannabinoids, including THC, THCA, 6a10aTHC, and CBD, as well as endocannabinoids like anandamide and 2-arachidonoylglycerol, and a synthetic cannabinoid called JWH018.
The results of the study showed that THC and its derivative both effectively inhibited the catalytic activity of the ATX enzyme in the assay. THCA also showed some inhibition, but to a lesser degree than the other two compounds. On the other hand, the synthetic cannabinoid and the two endocannabinoids had no significant impact on the enzyme's activity, and CBD only weakly affected one of the isoforms.
The researchers also aimed to understand how THC binds to ATX and inhibit its function. To do this, they used crystallographic data to create a three-dimensional molecular model of the binding interface between THC and ATX. The model showed that both THC molecules and 6a10aTHC molecules fit well against the active site of the enzyme, which confirms that the binding interface is a key mechanism for THC's ability to inhibit the enzyme's activity.
The study's findings suggest that THC may have potential as a drug development candidate for treating conditions that are associated with ATX activity such as cancer and inflammation. This is because the researchers have laid the molecular basis for explaining how THC interacts with ATX and inhibit its function.
ATX inhibitors could help combat glaucoma and fibrosis
The new research, published in Life Science Alliance, has found that THC can bind to the enzyme autotaxin (ATX) and inhibit its function. The study conducted by the European Molecular Biology Laboratory (EMBL) research team 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 ATX. The team also used crystallographic data to determine the three-dimensional structure of THC bound with ATX.
It is important to note that the researchers are cautious in interpreting their findings and emphasize that more research is needed to confirm whether the inhibition of ATX catalysis by THC and similar cannabinoids observed in vitro also holds true in vivo when cannabis products are consumed. However, they do point out that since ATX is already known to be present in human saliva and ATX expression has also been detected in salivary gland tissue, it is possible that cannabis smoke could come into contact with saliva and affect ATX-LPA signaling in vivo when cannabis is consumed via smoking.
The potential implications of these findings are significant as ATX inhibitors are already the subject of clinical trials and advanced research efforts. Studying the relationship between THC and ATX could 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. Additionally, several ATX inhibitors are currently being investigated as potential therapeutics for idiopathic pulmonary fibrosis.
The researchers suggest that THC may soon become an attractive candidate for drug development in these areas, as it is already FDA-approved and has a tolerable side-effect profile. They also posit that the findings may help explain the therapeutic effects of medical cannabis in glaucoma patients, as THC could feasibly reduce the formation of LPA by inhibiting the enzymatic activity of ATX.