Chelators: What is their mechanism of action?

Chelation of various sorts is something of enormous interest, especially when thinking about getting rid of some nasty substance or poison....

Everybody talks about the weather, but nobody is doing anything about it.. In a similar vein everyone talks about chelation, but nobody knows anything about it. In fact even with myself, I have really focused on understanding how the chelators work that I am interested in, but really have not looked in detail how other forms of chelation work. This is of particular interest to myself as it pertains to Gd and other heavy metals that can behave toxically.

So this blog really is a work in progress. One thing I will attempt to do is to categorize a number of them... but then over time try to figure out the basis of others.

Here goes:

In the early days of recognization that some linear agents can come apart somewhat readily in the body, the process of a chelator coming apart, for example Omniscan, is that the Gd dissociated from the ligand Diamide and then binds to some other particle like Phosphate, and this has been termed transmetalation - but this is really only part of the story. What is occurring is cation exchange.

Where one cation (Gd) is being exchanged on the ligand with another one: for example Ca. As we think about chelation though we recognize that a whole host of cations can be swapped out with Gd, both from the original parent GBCA ligand, but also on the other side with whatever anionic substrate the Gd is being bound to. In many respects it is like a modern stock exchange where cations and anionic substrates are in microseconds being swapped around until more stable species predominate (but not exclusively). So a classic stable swap out, cation exchange, is Gd splitting off from the GBCA ligand and binding to phosphate and the cation from the phosphate then attaching to the ligand. But it can be any cation that is residing in the body: so Mg, Mn, Zn, Fe, Cu, can all participate in the swap meet. No doubt other heavy metals that are also in the body, like lead, also are participating in this swap fest. This is probably in part where the synergistic toxicity with other heavy metals come in.

So DTPA and EDTA are both cation exchange chelators, and in many respects this form of chelation is the easiest to understand. This form of chelation is also generally a 1 for 1 exchange. The strength of the binding of cation to anionic substrate is described as the stability constant. In general the higher the stability constant of the ligand/ decorporation agent for the metal of interest, the better the cation exchange chelator is. But there are tremendous variations of how stable the bond is between cation exchange chelator and various cations. These agents are not metabolized to any extent and hence in general I very much prefer this concept.

In contrast the mechanism of action of the great chelation hope, HOPO is different. There is no exchange of cations but instead it binds Gd and other heavy metals with electrostatic forces, and ensnares the heavy metal by that fashion. So HOPO I term an electrostatic cloaking chelator. Now the developers of HOPO may prefer another term, but I think this sounds nice. Essentially the chelator cloaks the cation and holds it with electrostatic force, a process based on Coulomb's law. The remarkable property apparently of HOPO is that it is extremely effective at binding heavy metals like lead and Gd, but poor at binding native metals, like Mg, Mn, and Zn. This is quite ideal.

DMPS and DMSA are both rapidly metabolized in the body. A process which generally makes me nervous. DMSA is metabolized to mixed disulphides of cysteine, and DMPS is rapidly converted to its disulphide form. Heavy metals generally exist in cationic form , so at the present time I have not read enough (or interested enough since these are inferior chelators) to figure out exactly how they are removing heavy metals. I suspect as cation exchange chelators.

The same is true for other substances that are some form of detoxifying/ chelating agent. These include glutathione, NAC, Taurine, and Alpha Lipoic Acid. They may play a beneficial role to the primary chelation using either DTPA or HOPO. The primary chelators doing the heavy lifting of heavy metals out of the body, and the others may contribute some ancillary role. I do not recommend combining them in the same setting together, as I do not know what effect a powerful cation exchange chelator has on them, and they may serve to reduce the efficiency of chelation, by competing with Gd removal by the powerful chelator, or the creation of a toxic breakdown substance of the less potent chelator (eg Glutathione NAC).

Other compounds, a good example is activated charcoal, that is frequently used to bind orally ingested toxic/ poisonous substances adsorbs (that is, holds on its surface) toxic substances on its surface to promote removal. This form of chelation I term a physical entrapment chelator. The analogy for this is fly paper trapping flies on its gooey surface. At this time I am not well informed of the components and types of surface gooey-ness, and some we would have to image are not gooey but maybe are more spikey as the mechanism of adsorption. Activated charcoal seems to me a spikey adsorber. So activated charcoal is an adsorption-type physical entrapment chelator. Unlike cation exchange chelation this is not a 1 to 1 binding mechanism, and the number of particles may be in either direction, 1 particle chelator can pick up a number of toxic particles, or a number of chelator particles are needed to pick up 1 toxic particle, and I suspect based on the chelator. This would then be expressed as efficiency. Dietary substances such as zeolite, high fiber, pectin fruits (eg: peaches, nectarines, apricots) act as adsportion-type physical entrapment entities.

The related process is absorption, where the chelator takes up into its body the toxin. This would be termed absorption-type physical entrapment chelator. Infact this type of entrapment is what macrophages do in the body, but in that setting this is not termed chelation, although in reality is a form of chelation.

What is interesting in studying the detailed and extensive publication history of chelation (1950's- 2010) is that a few critical elements are either not understood or misunderstood. Two of the most critical being the role of le Chateliere's striving for equilibrium principle: that the bone reservoir is enormous for many heavy metals (notably Gd and lead) and is often most effectively removed by this principle. So authors in studies were disappointed that removal of heavy metals temporarily decreased blood and urine levels of heavy metals, but then they bounced back up. They bounced back up is a good thing, because it reflected the shifting of the heavy metal out of the most durable reservoir, bone, to more accessible reservoirs. Another misunderstanding is that prior authors claimed that heavy metals should not be removed when individuals were in an inflammatory state, because individuals reacted more often adversely with the intensifying of their symptoms. In fact the only clear reason to chelate is when an individual is in an inflammatory state, because that is when they actually have a Deposition DIsease of the metal. So there are approximately 340 million Americans in the Storage Condition state of lead , and maybe 200,000 in the Deposition Disease state - the only individuals who really benefit, and really need chelation are in the inflammatory or Deposition Disease state. The other striking absence in historic literature is the lack of understanding that it is Cytokines (and probably other inflammogens and alarmogens) that form the basis of the Disease state. It is these that need to be specifically dealt with in treatment.... And we are not there yet: knowing what cytokines to treat and how to do it. So when reading old literature it is critical to understand these huge limitations, and to take their findings with a grain of Gd.

The concept also of incorporating chelation strategies employing different mechanistic types of chelators is intriguing.

Chelators that are metabolized in the body frankly scare me. Also with other detoxifiers/chelators, because a chemical is known to have a certain role in the body, does not translate to mean that adding it into the picture will have any benefit. Often times the cells in the body, and the synergistic helping bacteria in the gut modify these substances, maybe through at least 4 enzyme steps, before they get it into the form that can be used. Simply jamming it into the vascular system very likely will not achieve that effect.

An early observation from work on the primitive chelators is that it is often important to start with low dose so subjects don't react with severe re-ignition of symptoms. This is something that I do routinely. (over the last 2 years). But what these researchers in early studies also did not realize, was not recognizing the role of cytokines and the host immune system, and that it is crucial to manage the Flare response. Flare was also not fully recognized, I think both because the chelators were not that effective, and that they were likely mainly chelating individuals in the Storage Condition and not the Deposition Disease state.

At the present time, the approach I favor is to use a powerful cation exchange chelator (DTPA), and it may make sense that individuals add in on their own gentle oral adsoption-type physical entrapment chelators (Metamucil, pectin containing fruits, high fibre foods (beans), pineapple for good measure). In the future the primary powerful chelator may be HOPO, or a combination of iv DTPA and then subsequent oral therapy with HOPO.

Richard Semelka, MD