HOPO. A more detailed look at the agent.

HOPO is a molecule that has been shrouded in mystery, even by experts in the field, into what it actually does. I have written earlier blogs on my interpretation of how HOPO acts, and it turns out my theories have been correct.

To start with, HOPO is a much larger and more complex molecule than DTPA, and many versions of HOPO have been created. Presently, the molecular form of HOPO considered the most effective as a decorporation agent is 1,2 HOPO and more refined as octadentate hydroxypyridonate ligand 3,4,3-LI(1,2-HOPO).. By the nature of the multiple possibilities of constructing HOPO and its activity, this may change with time. Because of its relatively large size and complexity for decades it has been considered a contamination clean-up agent for radioactive spills. It is only over the last decade has it been seriously looked at as an agent to be used in humans.

In contrast, DTPA used for chelation is a small and simple molecule and acts very simply as a cation exchange chelator forms an ionic bond bond with the metal in a 1 to one ratio: 1 DTPA to 1 atom metal. Metals with higher stability constant with DTPA are preferentially picked up and bound to DTPA. Gd and a number of other heavy metals have higher stability constant with DTPA than Ca or Zn, so they are preferentially taken up or transmetalized with DTPA. I prefer the term cation exchange than transmetalized as the concept is more clear.

As I opined in earlier blogs, and will more refine it in this blog, Gd does not form a chemical bond with HOPO, but rather it is sequestered by it. This sequestering could theoretically involved a greater ration of Gd or other heavy metals with HOPO. The development of HOPO as a Gd or other heavy metal sequestering agent relies on its ability to fold as a molecule. You may ask 'fold? How is folding something'. It turns out folding is a crucial property in many molecules, and for at least 1 decade the critical importance of folding in many proteins has been recognized. Nonfolding or malfolding of proteins can and does result in significant abnormalities and diseases in humans. The same is true for HOPO.

So proper folding is absolutely critical to the ability of HOPO to bind Gd or other heavy metals. One can think of HOPO as shaped like a soft taco containing shredded chicken as the Gd. The metal is held in place and retained by electrostatic forces (no sharing or exchanging of electrons, just the influence of them). This could be analogized as melted cheese lining the surface of the taco to hold the shredded chicken in place.

What is critical for all molecules that are used in humans is the ability of entry into various locations/ tissues. With an oral agent, to start with entry from the intestines into the vascular circulation of the body. This involves penetrating the intestinal lining and thenentry into blood vessels. The next critical step is the ability to penetrate through the endothelial lining of vessels and entry into the extracellular matrix (ECM) to pick up agent in the ECM. If it is unable to enter the ECM because it cannot penetrate the endothelial lining, the agent may still be able to peel off contaminant metals that themselves are stuck on the endothelial layer of vessels. Lastly it has to exit the body. Most chemicals exit by the kidneys, so they have to be a small enough size to be filtered by glomeruli in the kidneys (glomerular filtration). Some chemicals also exit by hepatobiliary route, and this requires that they be taken up intracellularly by hepatocytes.

As observed in the blockbuster Godzilla movie a couple of decades ago: SIZE MATTERS, in this case though the inverse of Godzilla, small size is very crucial to pass through all the above described gateways.

The size of particles regarding passage through the intestinal lining, through vascular lining, and glomerular lining is generally measured in the scale of nanometers. Daltons refers to atomic weight and in the size of these particles measured in kiloDaltons. Description of these sizes is beyond the scope of this blog - in the future I will address this. Other factors are involved in all these gateway passages, and in the intestinal lining whether an entity can follow along already existing pathways for incorporation.

To improve passage of molecules from the intestinal lumen, through the wall and into the circulation is generally referred to as bioavailability, the better the passage the higher the bioavailability. There is an entire field of science devoted to the development of agents that enhance bioavailability by facilitate in digestive system absorption of molecules/chemicals/drugs.

The development of metal chelating agents has been founded on the principles of: free of toxicity, high selectivity, and strong binding strength. What ofcourse we have learned over time the reality differs from the theoretical, The reality is relatively free of toxicity, strong binding strength, and the ability to be eliminated from the body. This is the trident of critical factors essential for a chelator for a certain metal. I would modify the first as really, very very relatively free of toxicity.

What I do find baffling is why DTPA has not been developed into an oral or suppository agent, as it should be no more complex than EDTA, and because of its smaller size should be considerably easier than HOPO. This will be a future subject.

So DTPA (EDTA, as well) are cation exchange chelators. HOPO sequesters cations by folding over them like a soft taco and holding them with electrostatic forces. DTPA achieves all 3 limbs of the chelate trident well. We are still in the process of evaluating the trident with HOPO, at this stage it appears relatively good, and the stability constant is supposed to be excellent. But evaluation is ongoing.

Richard Semelka, MD