Napoleon would be interested: An oxygen radicalistic view on Arsenic´s ambivalent role as poison and drug

History is full of mysterious poisonings. Among the victims are the protagonists of the most famous love story in literature. Of course I'm talking about Shakespeare's Romeo and Juliet. Two hostile families, a loving couple, no way out. So Romeo commits suicide after Julia’s alleged death by swallowing poison. However, which poison he took is not evident from Shakespeare's writings. At the end, beautiful Romeo is dying on the deathbed of his Juliet.

Oh Romeo! Did you know that Julia was not dead at all but only in deep sleep? You would have been surely sitting at the bedside and watched her asleep until she wakes up again. But we all know the true end: Romeo dies. Julia awakes, sees the dead Romeo and stabs herself with a knife. Tragic stories need a tragic end. At least in literature.

Later, Agatha Christie´s Miss Marple is very well known to solve her cases by even uncovering the real poisons used by the murderers such as taxane, cyanide, belladonna, and arsenic.

Arsenic, or its dissolved form arsenite, was considered from late antique to the 19th century as the murder poison par excellence. In the Medieval Ages, it received the telltale epithet "inheritance powder". Dissolved in alcohol, the white, odorless and rather difficult to taste powder could be administered unnoticed. A big glass of wine and depending on the dose of the poison, the enemy was gone; after hours, days, or sometimes weeks. Especially when given over time in steady doses, the visible effects of poisoning such as nausea, vomiting, diarrhea, convulsions, abdominal pain mimic usually other diseases such as influenza, or gastric ulcer.

The French emperor Napoleon, in his last years in exile on the island of St. Helena, was afraid of being poisoned by arsenic by his British captors. Indeed, samples of Napoleon’s hair showed high levels of arsenic; however, an autopsy after his death pointed to stomach cancer.

But what caused the cancer?

This may be the question of the hen and the egg. Nowadays we know that arsenic is frequently found as contaminant in drinking water. Large areas in India, Bangladesh, Argentina, Canada, Japan, China, Taiwan, Mexico, Chile, and the United States show arsenite concentrations in drinking water exceeding the safe limits. In Finland, the health impact was found to be insignificant.

If not causing death as a poison, arsenic ingestion is known to be related to heart disease, stroke, chronic lower respiratory diseases, diabetes and to cause cancer; for example of the skin, lung, liver, kidney, and stomach. The latter being the one Napoleon was diagnosed with after his death.

By contrast, arsenic is also long known to have general tonic and pain-relieving effects. It has been used as a drug, beauty powder, contraceptive, and as an anti-aging and doping agent for horses as well as a rat poison. In China arsenic is an ingredient of many traditional medicines used to treat e.g. syphilis, rheuma, asthma, swollen legs, abdominal pain, jaundice, vomiting, and even cancer. As an anti-cancer agent it has recently been approved as a standard therapy for the treatment of patients with relapsed or refractory acute promyelocytic leukemia in the United States and Europe. Those symptoms like swollen legs, abdominal pain, and jaundice were reported to be seen with Napoleon during his time in St. Helena and one could now argue whether he was even “doping” himself; a vicious circle could have emerged.

What makes arsenic ambivalent?

At the cellular level, arsenic induces formation of free radicals, and it can contribute to the inhibition of important enzymes. The generation of free radicals is a double-edged sword; at lower concentration they can reprogram the expression of various genes necessary for cell survival, whereas at high concentrations they cause lipid peroxidation, and damage of proteins and DNA, which consequently cause cell death.

Free radicals and a limited supply of oxygen play a role in tumor growth in which a specific protein called HIF-1α plays an important role. Although arsenic exerts some of its effects through formation of free radicals, it has never been explored how arsenic contributes to the regulation of HIF-1α under tumor promoting conditions like limited supply of oxygen.

In our study we found that under normal oxygen conditions, arsenic increased HIF-1α protein levels but under limited supply of oxygen it reduced HIF-1α. Interestingly, the arsenic effects were mediated at several levels. It seems that under normal oxygen conditions, arsenic causes formation of free radicals and consequently induces production of HIF-1α. This process was controlled by Nrf2, a protein which is sensitive to free radicals. Under limited supply of oxygen, less free radicals activate Nrf2 with the consequence that HIF-1α can no longer be produced. Consequently, tumor growth is strongly impaired.

While these findings do not answer whether Napoleon died “of arsenic poisoning or with arsenic medication”, they support that arsenic is an ambivalent molecule being associated with diseases such as cancer as well as being of therapeutic use. The above mentioned findings help to better understand the pro-carcinogenic mechanisms of arsenic, and at the same time they should foster the discussion and research to unravel more mechanistic aspects behind the anti-carcinogenic actions of arsenic.

And Napoleon? I think he would have found it interesting to learn that the poison which killed Romeo will forever remain a secret, and that other medications designed to combat disease have usually side-effects. Arsenic was likely just one of many other toxic substances impacting on the already troubled body of the former Emperor. It was said that he consumed sweet apricot-based drinks containing hydrocyanic acid and that he was treated with antimony containing emetics. Two days before his death, he received calomel, a mercury chloride containing laxative. Apparently, the loss of liquid and the resulting hypokalemia caused that he felt into a stupor and cardiac arrest. If only given arsenic, his cardiac system would likely have managed and he would have died “only“ from stomach cancer later on. Hence, Napoleon’s death was a case of “medical misadventure,” where large doses of arsenic, mercury- and antimony-containing medicines for his many ailments have had their contribution. Although, history is full of many more mysterious poisonings, for which facts are often hard to collect, they teach us new aspects even today. I am sure, Napoleon would be interested.

Thomas Kietzmann is a Professor in Cellular Biochemistry. The research of his group is dealing with oxygen sensing, redox regulation and various aspects of liver metabolism.