Sonic Hedghog and the Iron Fortress

Molecular mimickry - The Arsenic Files 3

The effects of inorganic arsenic, and its different forms (species), are so widespread at a cellular level, it is difficult to create a complete picture in one article. In this article we’ll look at four areas: 1) how arsenic interrupts the processes cells use to make energy, 2) the effects of arsenic on two major detoxification molecules, 3) how arsenic affects iron based molecules used for detoxification, creating energy and signalling that a cell needs to die, and 4 ) the effect of arsenic on DNA and how that leads to abnormal mutations and growth.

A recap

There are three routes of exposure to Arsenic. The first is ingestion in to the stomach and duodenum for uptake by the liver, and excretion by the kidneys. The next route, for treatment of Acute promyelocytic leukemia (APL), is through injection or infusion in to a vein, flowing through the liver to bone marrow or kidneys, to the heart, lungs, heart and around again. The third route is gas exchange through the lungs, heart and around the body. If arsine gas enters the bloodstream from the lungs it converts to arsenic trioxide as it travels round the oxygen rich environment. This last route is the only one that makes it all the way round the body before it reaches the liver, with lots of opportunity to divert in to cells along the way.

In the liver arsenic is converted to Monomethylarsinic acid (MMA) and Dimethyarsinous acid (DMA) through a process called methylation. All compounds reaching the liver undergo ‘redox’ processes to allow toxins to be expelled and useful compounds to be recycled. Arsenic pentoxide is reduced to arsenic trioxide. It is then methylated and reduced again to produce MMA (III), DMA(V) and DMA (III).

Initial research believed that arsenic methylation in the liver made it harmless and ready for excretion. More recent research strongly suggests the methylation process could make arsenic even more toxic to cells. We will look at this more in the section on DNA. It is unclear if arsenic trioxide immediately converts to MMA/DMA as soon as it gets to the liver. Other possibilities are it being absorbed by liver cells (hepatocytes) as trioxide or methylates, damaging them and harming the methylation and other crucial processes. Some arsenic trioxide may find its way straight to the gut with methylates and, depending on diet, be reabsorbed. Compounds also likely make their way to the bone marrow along with heme. Arsenic compounds are considered fairly unstable, meaning chemical activity in the cells could convert one form in to another. What goes on in the cell stays in the cell!

Measuring exposure

How does standard exposure and elimination data compare to more detailed studies? The generally accepted rate of excretion through urine is a reduction by half every 6 hours approximately (half-life). Methylates of arsenic have a half-life of 20-30 hours. None of these estimates consider what happens to the gas form of arsenic before it gets to methylation stage. Measurement of exposure to the gas is even more problematic. Only arsine gas detectors and dosimeters (similar to those ones used in xray departments) would be able to measure exposure accurately over time.

Let’s have a look at how these figures stack up in documented experiments.

One experiment measures the different arsenic types excreted in urine after arsenic trioxide was administered. Patients excreted between 32 and 65% after 24 hours. The paper author assumes the much lower presence of arsenic methylates was due to the high level of arsenic trioxide used, which must have prevented arsenic methylation. However, as between 35% and 68% remains unaccounted for, might it be possible the methylates were actually produced by the liver and are still in the patients bodies somewhere.

In this paper on treating relapsed APL using arsenic trioxide, of a 10mg daily dose only 1-8% of the dose was excreted in urine by the end of 24 hours. Nails, hair and urine showed a 5 to 7 fold increase in arsenic trioxide passage or storage. This implies that hair and nails can be no more than 8% or 7 fold per day. This means that only 24% maximum can have been excreted to the urine, hair and nails per day. This leaves 76% unaccounted for. Therefore, traditional estimates of a total 70% excretion of arsenic through urine is suspect, as urine is meant to be clear of arsenic in 3 days. This would mean excretion must be a bare minimum 23% per day in urine to achieve that figure. So where is the rest of it going?

Baking a Cake

Let’s imagine that creating energy in our cells is a bit like baking a cake. In order for the cake to come out perfectly you need a recipe and the right ingredients, bonded together in the right way. They have to be added in the right order, mixed correctly, cooked correctly. Too much or too little mixing, putting an ingredient in too early, leaving an ingredient out entirely, substituting an ingredient, using poor quality ingredients, or even not turning on the oven, could all lead to a failed cake. This is how it is in our cells. For everything to work properly, everything has to be present and correct, and mixed in the right order at the right temperature for things to work out well. So what happens when arsenic sneaks in to our list of ingredients?