The Right Chemistry: Sometimes luck serves as a springboard for science

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It is a lifesaver, stocked in every emergency room! N-acetylcysteine (NAC) is amazingly effective as an antidote to acetaminophen poisoning.

Better known by the trade name Tylenol, acetaminophen over-the-counter pain and fever relievers account for roughly 50 per cent of all cases of acute liver failure. The majority is because of accidental overdose based on the belief that when it comes to pain relief, more is better. But a frightening number of cases, especially among the young, are the result of attempted self-harm.

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The discovery of NAC as an antidote is a fascinating story laced with serendipity.

“A lucky accident dropped the medicine into our hands,” reported physicians Arnold Cahn and Paul Hepp in a German medical journal in 1886.

After diagnosing intestinal worms in a patient, they prescribed naphthalene, the usual remedy at the time. However, the chemist who dispensed the medication made a mistake and filled the prescription with acetanilide, a compound that had first been synthesized in 1852 by Charles Gerhardt from aniline extracted from coal tar. Chemists stocked this chemical because of much interest in aniline derivatives after William Henry Perkin’s famous accidental 1856 discovery of the dye mauve as he was attempting to convert aniline into quinine, which was in great demand for the treatment of malaria.

Acetanilide had no effect on the worms, but it did reduce the patient’s fever.

As chance would have it, Hepp’s brother worked for a pharmaceutical company that was interested in pursuing this observation. The fever-reducing ability of acetanilide was confirmed, and the drug hit the market as “Antifebrine.”

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This caught the attention of Carl Duisberg, a chemist at the Friedrich Bayer Company, a dye manufacturer. The company had a giant waste heap of nitrophenol, a byproduct of dye production, for which it was trying to find a use. Duisberg now realized that nitrophenol could readily be converted into various compounds that had a molecular structure similar to acetanilide. Maybe these, he thought, would allow the company to get into the pharmaceutical business.

Indeed, one compound turned out to be a more powerful fever reducer than acetanilide and as a bonus did not have the side-effect of reducing the oxygen-carrying ability of the blood, a problem with which acetanilide was saddled. Named “phenacetin,” the drug became a huge success.

It wasn’t until 1947 that it became apparent that acetanilide and phenacetin reduced fever for the same reason. In the body, both are converted into acetaminophen, the actual active agent. Curiously, acetaminophen had been synthesized back in 1877 by Harmon Northrop Morse at Johns Hopkins University, and in 1893 had even been tried by German physician Joseph von Mering as a pharmaceutical.

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Although it reduced fever, it never made it to market because von Mering claimed that, like acetanilide, it reduced the oxygen-carrying ability of the blood. It seems this was not investigated further because of von Mering’s eminence. The scientific community had been captivated by his removal of the pancreas of a dog and noting that it frequently urinated on the floor even though it was house trained. Testing of the dog’s urine revealed a high level of sugar and led von Mering to conclude that the pancreas controls blood sugar levels. If this exalted physician said that acetaminophen was not suitable as a drug, then it wasn’t.

That view was not challenged until finding acetaminophen to be the active metabolite of both acetanilide and phenacetin precipitated an investigation of von Mering’s claim, which turned out to be unfounded. By the 1950s, pharmaceutical companies in Britain and the U.S. had seized the opportunity to market acetaminophen as a fever and pain reducer, touting its superiority to both phenacetin and Aspirin. Phenacetin had been linked with kidney disease, and Aspirin, introduced by the Bayer Company back in 1899, had gastrointestinal side-effects.

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Acetaminophen sales were rolling along merrily until cases of liver toxicity from overdose were noted in the late 1960s. There was no known remedy and patients were dying. Once again, fate stepped in. A chance discovery, reported in 1973, led to the effective treatment of an overdose. Working at the National Institutes of Health in the U.S., Jerry Mitchell and David Jollow were studying the toxicity of bromobenzene, an industrial chemical. Their research had nothing to do with acetaminophen, but they came upon a paper by another group of scientists who had been studying the effect of various substances on the activity of known cancer-causing agents.

Acetaminophen, by then a very popular drug, was one of the substances they investigated and found that it interfered with the activity of enzymes that normally attach molecules to toxins allowing them to be ferried out of the system. On learning this, Mitchell and Jollow wondered if acetaminophen would also have an effect on the toxicity of bromobenzene. They injected some rats with bromobenzene, some with bromobenzene plus acetaminophen, and others with just acetaminophen. Much to their surprise, acetaminophen alone had the greatest effect, causing liver damage in the rats.

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Now the question was how was this happening? It turned out that acetaminophen itself was not the culprit. Once ingested, it was metabolized into a compound that reacts with proteins in the liver causing the damage. Normally the body can eliminate the culprit in the urine by binding it with glutathione, one of the body’s natural detoxicating substances. However, in the case of an overdose, stores of glutathione run out and liver damage ensues. The obvious remedy? Boost glutathione levels.

Glutathione is composed of three amino acids linked together in a “tripeptide” and can be easily produced in the lab but does not make it into the bloodstream if taken orally. Two of glutathione’s amino acids are plentiful in the body, but cysteine is found in smaller amounts and is the limiting factor when it comes to the body’s ability to make glutathione.

Unfortunately, cysteine does not work as an oral supplement either because it cannot stand up to the acidic environment of the stomach. But it turned out that attaching an acetyl group to the nitrogen atom in cysteine results in N-acetylcysteine that survives digestion and is absorbed into the bloodstream where it liberates cysteine to be absorbed by cells that can then use it to make glutathione. Intravenous NAC is almost guaranteed to be life saving if infused within 10 hours of an overdose.

An obvious question now arises. Why is NAC not incorporated into acetaminophen pills to reduce potential toxicity? Good question. For one, pharmaceutical companies are not particularly eager to call attention to possible risks. More significantly, NAC is relatively unstable and breaks down with time when exposed to air. Still, one would think that there are enough clever chemists out there who could figure out a way to incorporate NAC into acetaminophen tablets to make them safer. Maybe we need another lucky discovery.

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Joe Schwarcz is director of McGill University’s Office for Science & Society (mcgill.ca/oss). He hosts The Dr. Joe Show on CJAD Radio 800 AM every Sunday from 3 to 4 p.m.

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