Toward a safer form of acetaminophen

July 10, 2013
Toward a safer form of acetaminophen

Efforts to develop a safer form of acetaminophen—the pain and fever-reducer that is one of the most widely used drugs—have led to discovery of substances that may have less potentially toxic effects on the liver. A report on the research appears in ACS Medicinal Chemistry Letters.

Roman Shchepin and colleagues explain that a link exists between acetaminophen and liver damage. The damage may be severe and can occur with intentional and accidental overdoses, as well as when susceptible individuals take the drug. Indeed, acetaminophen has been implicated in almost 50 percent of all cases in the United States alone. Scientists have known the biochemical basis of acetaminophen's , and Shchepin and colleagues set out to develop safer versions of acetaminophen.

They describe the design and testing of two compounds that have a similar architecture to acetaminophen, but aren't toxic to grown in the laboratory. The researchers say that, although further testing is needed, these compounds are promising candidates for acetaminophen replacements.

Explore further: FDA group recommends acetaminophen liver warnings

More information: "Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues" ACS Med. Chem. Lett., Article ASAP DOI: 10.1021/ml4000904

Abstract
Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intramolecular electron transfer that generates the Tyr385 radical required for abstraction of a hydrogen from arachidonic acid to initiate prostaglandin synthesis. Unrelated to this pharmacological action, metabolism of ApAP by CYPs yields an iminoquinone electrophile that is responsible for the hepatotoxicity, which results from high doses of the drug. We synthesized novel heterocyclic phenols predicted to be electron donors. Two of these inhibited the oxygenation of arachidonic acid by PGHS-1 and myoglobin and also were shown to be more metabolically stable and exhibited less direct cytotoxicity than acetaminophen. They are leading candidates for studies to determine whether they are free of the metabolism-based hepatotoxicity produced by acetaminophen.

Related Stories

FDA group recommends acetaminophen liver warnings

May 27, 2009

(AP) -- A Food and Drug Administration report released Wednesday recommends stronger warnings and dose limits on drugs containing the painkiller acetaminophen, citing an increased risk of liver injury.

Patients may receive too much acetaminophen in hospital

May 23, 2012

(HealthDay) -- Roughly 2.5 percent of admitted hospital patients may receive more than the safe daily cumulative dose of the pain-reliever acetaminophen, best known as Tylenol, on at least one day, according to a new U.S. ...

Dietary supplements can cause liver injury, warns expert

October 29, 2012

Dose-dependent (acetaminophen) and idiosyncratic drug-induced liver injuries (DILI) are the leading cause of acute liver failure in the United States and are responsible for approximately 50 percent of all reported cases.

Doubling up on cold, flu remedies may harm liver

January 30, 2013

(HealthDay)—Taking too much acetaminophen, an active ingredient in many commonly used drugs for fever and pain relief, including Tylenol, can cause liver damage, experts at the U.S. Food and Drug Administration warn.

Recommended for you

Isolation of Fe(IV) decamethylferrocene salts

August 29, 2016

(Phys.org)—Ferrocene is the model compound that students often learn when they are introduced to organometallic chemistry. It has an iron center that is coordinated to the π electrons in two cyclopentadienyl rings. (C5H5- ...

Bringing artificial enzymes closer to nature

August 29, 2016

Scientists at the University of Basel, ETH Zurich, and NCCR Molecular Systems Engineering have developed an artificial metalloenzyme that catalyses a reaction inside of cells without equivalent in nature. This could be a ...

New method developed for producing some metals

August 25, 2016

The MIT researchers were trying to develop a new battery, but it didn't work out that way. Instead, thanks to an unexpected finding in their lab tests, what they discovered was a whole new way of producing the metal antimony—and ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.