Exploring chronic disease
19 Jul 2008
By this point, people familiar with the Marshall pathogenesis realize that the Vitamin D Receptor plays an extremely important role in activating immune function and keeping the chronic, intraphagocytic bacteria that cause inflammatory disease under control.
But when the vitamin D feedback pathways fleshed out by Marshall in a recentBioEssays paper are examined, another important receptor enters the picture.It goes by the name of the Pregane X Receptor (PXR), and like the VDR, the PXR is also a nuclear receptor. Mainstream researchers generally understand that the PXR plays an important role in regulating the metabolism, transport, and excretion of exogenous compounds, steroid hormones, vitamins, bile salts, and xenobiotics (chemicals that are foreign to the body). However, they are only recently beginning to understand that the receptor is also intricately connected to VDR function, vitamin D metabolism, and proper regulation of the vitamin D metabolites.
The PXR is unique in the sense that its ligand binding pocket (the place where other molecules can dock into the receptor) enlarges to allow for activation by large molecules or shrinks to accommodate smaller molecules such as the steroids.
Marshall’s model of vitamin D metabolism predicts that blockage of the VDR will cause problems with the feedback pathways that keep levels of the vitamin D metabolites 25-D and 1,25-D in the correct range. To be more specific, when the VDR is blocked by bacterial substances and 25-D, it can not longer transcribe an important gene that under normal circumstances allows for the transcription of CYP24A1, an enzyme whose role is to inactivate excess 1,25-D. However, while it is the VDR’s job to transcribe the gene for CYP24A1, the PXR actually induces transcription, or actual creation, of the enzyme. This means that any molecule capable of slowing the activity of the PXR also allows for less production of CYP24A1.
The consequences of the above are two-fold. If the VDR is blocked, it will transcribe the gene for CYP24A1 at a greatly reduced rate. If the PXR is blocked, the actual creation of the enzyme will be thwarted as well. Under such circumstances, the amount of CYP24A1 in the tissues drops significantly, meaning that 1,25-D is able to reach unnaturally high levels without any system to keep it in check.
But what blocks the PXR? After deriving data from a structural model of the PXR that has just been published, Marshall used nuclear receptor modeling to show that 1,25-D binds the PXR and slows its activity, acting as a strong antagonist. According to Marshall, “[1,25-D] almost certainly will competitively displaces the native ligand(s) [of the PXR] at physiologic concentrations.” This means that high levels of 1,25-D slow PXR activity, blocking production of the CYP24A1 that would otherwise cause 1,25-D to be broken down to other forms of vitamin D.
Still, a skeptic might ask, “Besides Marshall’s in silico data, how do we know that 1,25-D inactivates the PXR causing a drop in the production of CYP24A1?”
In a study recently published in BMC Evolutionary Biology researchers performed a detailed analysis of molecules that activate the PXR. They ended up detecting numerous compounds that activate (serve as agonists) of the receptor. Interestingly, 25-D and 1,25-D were not among the compounds that they found to be PXR agonists. This strongly suggests that, as Marshall puts forth, the vitamins D do indeed serve as antagonists of the PXR.
“Of interest is that they found that 1,25-D and 25-D were not agonists. Since my in-silico work has identified the very high affinity they have for the PXR, it follows that they must be antagonists, which is what I had deduced and published in figures 1 and 2 of my paper [BioEssays 2008],” states Marshall.
One of the PXR agonists detected by the team was Hyperforin, or St John’s Wort. Now that it is confirmed as a PXR target, Marshall warns against its use, essentially because any molecule that interferes with the receptors that control the vitamin D receptors is likely to dysregulate immune function.The team also noted that another primary target of the PXR is rifampicin. Since rifampicin (a drug often used to treat infections) is derived from streptococcal bacteria, one could say that the PXR is essentially activated by a pathogen, a reality compatible with the fact that pathogens themselves can directly affect the body’s receptors and feedback pathways. Furthermore, the PXR is also strongly activated by dioxin, a compound that has been linked to an increased risk of cancer. According to Marshall, the fact that dioxin binds the PXR with such a high affinity provides a possible pathway for how the substance causes damage to the immune system.
The VDR and PXR work in such a symbiotic fashion that the two receptors likely evolved from the same base structures. Such PXR/VDR homology fits nicely with Marshall’s view of the immune system. When asked about the immune system, Marshall emphasizes that it was not designed in order to accomplish specific tasks – its creation was never planned. Rather, it simply evolved. Because evolutionary processes are ruled by chance, not everything a particular receptor or cell type does is necessarily beneficial. Yet, it can be assumed that those components of the immune system that remain with us today exist because the bulk of what they do is useful. Certainly the majority of functions performed by the VDR and the PXR are critical to our well being.
Amy Proal graduated from Georgetown University in 2005 with a degree in biology. While at Georgetown, she wrote her senior thesis on Chronic Fatigue Syndrome and the Marshall Protocol.