How Glutamine Can Aid Acetaminophen Overdose
An interview with H. Frederik Nijhout, PhD, Professor of Biology at Duke University, Durham, North Carolina.
One out of 4 Americans take an acetaminophen product at least once a week, making it the most widely used drug in the country. Acetaminophen is found in Tylenol and many over-the-counter and prescription medicines. This makes acetaminophen overdoses a common problem. Every year, more than 44,000 people end up in the emergency room with acetaminophen overdose and around 400 die.
These days, the standard emergency protocol for counteracting acetaminophen (APAP) overdose is to administer N-acetylcysteine (NAC), known by its brand name Acetadote. It helps replenish cysteine, an important amino acid and key ingredient to glutathione (GSH), an antioxidant that gets heavily depleted as the body fights off the toxins flooding the liver during an overdose.
But cysteine may not be the only amino acid in short supply during an APAP overdose. Researchers at Duke University believe that glutamate may be another key ingredient that becomes compromised as the body starves for more GSH.
Could this mean the next best antidote for APAP overdose would be a kind of cysteine/glutamine cocktail? Apparently, it isn’t a far-fetched idea at all, according to H. Frederik Nijhout, PhD, a professor of biology at Duke University in Durham, North Carolina.
“In fact, that is exactly why we started these studies. We thought there has got to be a better way to treat poisoning cases than to shoot people up with the largest dose of NAC they can tolerate,” Dr. Nijhout told Practical Pain Management.
Glutamine's Role As Antioxidant
Glutamine is an important amino acid that immunological cells consume.1 It’s no coincidence then that glutamine becomes depleted in acute catabolic states, like sepsis, burns, and starvation.2 Indeed, clinicians already have found that glutamine supplementation improves outcomes for trauma, major surgery, burns, and of course, APAP overdose.3-5
When an APAP overdose occurs, the body uses the “master antioxidant” GSH to filter out the hepatotoxic byproduct NAPQI, but when there’s an exceptional amount of acetaminophen in the body, there’s simply not enough GSH to go around. That left over NAPQI then starts binding to hepatocytes and inducing necrosis and inflammation,6 which can be deadly.
In the current study, Dr. Nijhout and his colleagues sought to better understand the mechanics of GSH metabolism, especially in the context of an APAP overdose.7 They crafted a mathematical model, a set of differential equations that tracked and measured the concentrations of various substrates in the liver, skeletal muscle, and blood plasma in rats.
A previous animal study found that rats supplemented with glutamine had maintained far less depleted GSH levels during an APAP overdose compared to controls.5 Using their mathematical model, Dr. Nijhout and colleagues now believe they understand exactly why extra glutamine comes in handy during an APAP overdose.
"We show that for the normal rat, the model solutions fit experimental data including the diurnal variation in GSH. We show that for the rat chronically dosed with dexamethasone [an artificial glucocorticoid which induces a catabolic state] the model can be used to explain empirically observed facts such as the linear decline in intramuscular Gln and the drop in plasma glutamine," wrote the researchers.7
Current ER protocol administers NAC to supplement cysteine levels in the body, which keeps GSH levels up. However, glutamate, whose precursor is glutamine, is also a key ingredient to GSH. As cysteine levels deplete, a cystine-glutamate antiporter does a kind of “trade-off,” transporting glutamate out of the liver to grab more cystine (oxidized cysteine) from blood plasma. Consequently, this trade-off spends a lot of glutamate, which leads to glutamate levels running dry, as well.
When Dr. Nijhout included this theory into the equations, the data matched right up with those past findings. It served to explain why rats that had been given extra glutamine fared better during an overdose. Of course, there’s still much more to figure out, especially since results could differ with other strains of rat, or female rats, for that matter.
An experimental study is the next step, as Dr. Nijhout said he plans to work alongside liver pathology experts at the Duke Medical Center for further investigations, with the aim of developing a more effective antidote.
Future Research Plans
“So our overall plan is to come up with a principled way of estimating the correct antidote dosing, including the use of an NAC/glutamine cocktail. But that is some way off in the future,” said Dr. Nijhout
But Dr. Nijhout's research could lead to far more than a recipe for a better APAP antidote. Glutamine supplementation has shown evidence of stemming the depletion of skeletal muscle in various other catabolic states, which could mean better future treatments for many other conditions.
Dr. Nijhout and his team hope to employ their new mathematical model to a wider therapeutic arena, as it may yield further insight into how oxidative stress affects the body in acute states, and how supplementing glutamine could make an important difference.
The study was supported by grants from the National Science Foundation, the National Institutes of Health, and the Division of Mathematical Sciences. The authors declared no conflicts of interest.